(6R,10R)-6,10,14-trimetylpentadecan-2-one prepared from 6,10-dimetylundec-5-en-2-one or 6,10-dimetylundeca-5,9-dien-2-one

ABSTRACT

The present invention relates to a process of manufacturing (6R,10R)-6,10,14-trimetylpentadecan-2-one in a multistep synthesis from 6,10-dimetylundec-5-en-2-one or 6,10-dimetylundeca-5,9-dien-2-one. The process is very advantageous in that it forms in an efficient way the desired chiral product from a mixture of stereoisomers of the starting product.

This application is the U.S. national phase of International ApplicationNo. PCT/EP2013/077187 filed 18 Dec. 2013 which designated the U.S. andclaims priority to EP Patent Application No. 12197835.7 filed 18 Dec.2012, the entire contents of each of which are hereby incorporated byreference.

TECHNICAL FIELD

The present invention relates to the field of(6R,10R)-6,10,14-trimethylpentadecan-2-one and the reaction productsthereof.

BACKGROUND OF THE INVENTION

(6R,10R)-6,10,14-Trimethylpentadecan-2-one is an important intermediate,particularly for the synthesis of (R,R)-isophytol[=(3RS,7R,11R)-3,7,11,15-tetramethylhexadec-1-en-3-ol], (R,R)-phytol andtocopherols.

Isophytol, phytol and tocopherols are chiral substances, the latter twoof which occur in nature in the form of the “all-R” stereoisomer. Phytolcontains 2 stereocentres and in addition a trisubstituted carbon-carbondouble bond which gives rise to E/Z-steroisomers, while isophytol andtocopherols have 3 stereocentres. Therefore, there are multiple isomers.

It has been shown that of the naturally occurring stereoisomers oftocopherols, (2R,4′R,8′R)-tocopherols, particularly(2R,4′R,8′R)-α-tocopherol, have the highest bioactivity (biopotency).

As natural sources of (2R,4′R,8′R)-tocopherols and (R,R)-phytol,however, are very limited, the market has a strong need for an effectivesynthesis of (2R,4′R,8′R)-tocopherols and (R,R)-isophytol and(6R,10R)-6,10,14-trimethylpentadecan-2-one, the starting material ofthese products, which is useful for industrial scale application.

As, furthermore, higher bioactivity (biopotency) has been shown, forexample by H. Weiser et al. in J. Nutr. 1996, 126(10), 2539-49, to occurin general by tocopherols having the R-configuration at the chiralcentre situated next to the ether oxygen atom in the ring of themolecule (i.e. 2R-configuration), as compared to the correspondingisomers having S-configuration, there is a strong need for an effectiveand industrial scale synthesis of (2R,4′R,8′R)-tocopherols, particularly(2R,4′R,8′R)-alpha-tocopherol.

SUMMARY OF THE INVENTION

Therefore, the problem to be solved by the present invention is to offera process for the manufacturing(6R,10R)-6,10,14-trimethylpentadecan-2-one.

Surprisingly, it has been found that the process according to claim 1 isable to solve this problem. It has been shown that it is possible toobtain one specific isomer of interest from a mixture of isomers ofstarting material, i.e. a mixture of (E)-6,10-dimethylundec-5-en-2-oneand (Z)-6,10-dimethylundec-5-en-2-one or a mixture of(E)-6,10-dimethylundeca-5,9-dien-2-one and(Z)-6,10-dimethylundeca-5,9-dien-2-one.

Preferred embodiments of the inventions allow making use of thenon-desired isomers, by using a cis/trans-isomerization. The asymmetrichydrogenation, which is one of the key elements of this invention, canbe improved in quality and speed by ketalization of the ketones to beasymmetrically hydrogenated as well as by the use of specific additives.

The process of the invention allows the production of the targetmolecules efficiently in a high quality from isomeric mixtures, allowingit to be used for industrial scale production. The process is veryadvantageous in that it forms the desired chiral product from a mixtureof stereoisomers of the starting product in an efficient way.

Further aspects of the invention are subject of further independentclaims. Particularly preferred embodiments are subject of dependentclaims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 to 3 show subsequent steps from both6,10-dimethylundec-5-en-2-one and 6,10-dimethylundeca-5,9-dien-2-one to(6R,10R)-6,10,14-trimethylpentadecan-2-one;

FIG. 4 shows the subsequent steps from(6R,10R)-6,10,14-trimethylpentadecan-2-one to (R,R)-isophytol,(2-ambo)-α-tocopherol and (2R,4′R,8′R)-α-tocopherol, respectively;

FIGS. 5 and 6 show embodiments of asymmetric hydrogenations relating tothe process steps shown in FIGS. 1 and 3, respectively; and

FIG. 7 shows chromatograms for the (2-ambo)-α-tocopherol of experimentE7.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect the present invention relates to a process ofmanufacturing (6R,10R)-6,10,14-trimethylpentadecan-2-one in a multistepsynthesis from 6,10-dimethylundec-5-en-2-one or6,10-dimethylundeca-5,9-dien-2-one comprising the steps

-   -   a) providing a mixture of (E)-6,10-dimethylundec-5-en-2-one and        (Z)-6,10-dimethylundec-5-en-2-one or a mixture of        (E)-6,10-dimethylundeca-5,9-dien-2-one and        (Z)-6,10-dimethylundeca-5,9-dien-2-one;    -   b) separating one isomer of 6,10-dimethylundec-5-en-2-one or of        6,10-dimethylundeca-5,9-dien-2-one from the mixture of step a)    -   c) asymmetric hydrogenation using molecular hydrogen in the        presence of achiral iridium complex and yielding        (R)-6,10-dimethylundecan-2-one;    -   d) chemically transforming (R)-6,10-dimethylundecan-2-one to a        mixture of (R,E)-6,10,14-trimethylpentadec-5-en-2-one and        (R,Z)-6,10,14-trimethylpentadec-5-en-2-one;    -   e) separating one isomer of        (R)-6,10,14-trimethylpentadec-5-en-2-one from the mixture        obtained in step d)    -   f) asymmetric hydrogenation using molecular hydrogen in the        presence of a chiral iridium complex and yielding        (6R,10R)-6,10,14-trimethylpentadecan-2-one;    -   wherein the steps a)-f) are in the order a, b, c, d, e, f.

The term “independently from each other” in this document means, in thecontext of substituents, moieties, or groups, that identicallydesignated substituents, moieties, or groups can occur simultaneouslywith a different meaning in the same molecule.

A “C_(x-y)-alkyl” group is an alkyl group comprising x to y carbonatoms, i.e., for example, a C₁₋₃-alkyl group is an alkyl groupcomprising 1 to 3 carbon atoms. The alkyl group can be linear orbranched. For example —CH(CH₃)—CH₂—CH₃ is considered as a C₄-alkylgroup.

A “C_(x-y)-alkylene” group is an alkylene group comprising x to y carbonatoms, i.e., for example C₂-C₆ alkylene group is an alkyl groupcomprising 2 to 6 carbon atoms. The alkylene group can be linear orbranched. For example the group —CH(CH₃)—CH₂— is considered as aC₃-alkylene group.

A “phenolic alcohol” means in this document an alcohol which has ahydroxyl group which is bound directly to an aromatic group.

The term “(R,R)-isophytol” used in this document means(3RS,7R,11R)-3,7,11,15-tetramethylhexadec-1-en-3-ol).

The term “(R,R)-phytol” used in this document means(2E,7R,11R)-3,7,11,15-tetramethyl-2-hexadecen-1-ol).

Substance names starting with “poly” such as polythiol as used in thepresent document refer to substances formally containing two or more ofthe corresponding functional groups per molecule.

The term “stereogenic centre” as used in this document is an atom,bearing groups such that interchanging of any two of the groups leads toa stereoisomer. Stereoisomers are isomeric molecules that have the samemolecular formula and sequence of bonded atoms (constitution), but thatdiffer in the three-dimensional orientations of their atoms in space.

The configuration at a stereogenic centre is defined to be either R orS. The R/S-concept and rules for the determination of the absoluteconfiguration in stereochemistry is known to the person skilled in theart.

In the present document a carbon-carbon double bond is defined as being“prochiral” if addition of molecular hydrogen to said carbon-carbondouble bond leads to the formation of a stereogenic carbon centre.

Cis/trans isomers are configurational isomers having differentorientation at the double bond. In this document the term “cis” isequivalently used for “Z” and vice versa as well as “trans” for “E” andvice versa. Therefore, for example the term “cis/trans isomerizationcatalyst” is equivalent to the term “E/Z isomerization catalyst”.

A “cis/trans isomerization catalyst” is a catalyst which is able toisomerize a cis isomer (Z-isomer) to a cis/trans isomer mixture (E/Zisomer mixture) or to isomerize a trans isomer (E-isomer) to a cis/transisomer (E/Z isomer mixture).

The terms “E/Z”, “cis/trans” and “R/S” denote mixtures of E and Z, ofcis and trans, and of R and S, respectively.

In case identical labels for symbols or groups are present in severalformulae, in the present document, the definition of said group orsymbol made in the context of one specific formula applies also to otherformulae which comprises said same label.

In the present document any single dotted line represents the bond bywhich a substituent is bound to the rest of a molecule.

“Assay yield” of an asymmetric hydrogenation is in the presentapplication the molar ratio of number of molecules of completelysaturated ketones or aldehydes or ketals or acetals to the number ofmolecules of unsaturated ketones or aldehydes or ketals or acetals beingsubmitted to the hydrogenation.

6,10-Dimethylundec-5-en-2-one is a known substance and can, for example,be synthesized from 3,7-dimethyloct-1-en-3-ol and 2-methoxyprop-1-ene asdisclosed in DE 1193490. 3,7-Dimethyloct-1-en-3-ol can, for example, besynthesized according to the procedure disclosed in WO 2012/025559 A2.The entire content of DE 1193490 and WO 2012/025559 A2 is herebyincorporated by reference.

6,10-Dimethylundec-5-en-2-one is a mixture of(E)-6,10-dimethylundec-5-en-2-one and (Z)-6,10-dimethylundec-5-en-2-one.

6,10-Dimethylundeca-5,9-dien-2-one is commercially available and can be,for example, synthesized from linalool by the Carroll rearrangement, andis a mixture of (E)-6,10-dimethylundeca-5,9-dien-2-one and(Z)-6,10-dimethylundeca-5,9-dien-2-one.

In a first step (step a) of the process a mixture of(E)-6,10-dimethylundec-5-en-2-one and (Z)-6,10-dimethylundec-5-en-2-oneor a mixture of (E)-6,10-dimethylundeca-5,9-dien-2-one and(Z)-6,10-dimethylundeca-5,9-dien-2-one is provided.

Separation

Steps b) and e) relate to the separation of one of the isomers of6,10-dimethylundec-5-en-2-one or of 6,10-dimethylundeca-5,9-dien-2-onefrom the mixture of step a) and to the separation of one of the isomersof (R)-6,10,14-trimethylpentadec-5-en-2-one from the mixture obtained instep d), respectively.

This separation of isomers in step b) and/or e) can be done in differentways. A first possibility is the separation by means of chromatography.A further and preferred way of separation is that the separation ofisomers in step b) and/or e) is done by distillation. The separation ispossible by the fact that the isomers have different boiling points. Inorder to minimize thermal degradation of the isomers it is advisable todistil under reduced pressure and by means of a distillation column.

As the isomers to be separated have different boiling points (seetable 1) the isomers can be separated by distillation. Using specificdistillation techniques and equipment it is possible to separate theisomer having the higher or the lower boiling point.

TABLE 1 Boiling points of isomers. Substance Boiling point(E)-6,10-dimethylundec-5-en-2-one 112° C. at 5 mbar(Z)-6,10-dimethylundec-5-en-2-one 109° C. at 5 mbar(E)-6,10-dimethylundeca-5,9-dien-2-one 78° C. at 0.5 mbar(Z)-6,10-dimethylundeca-5,9-dien-2-one 75° C. at 0.5 mbar(R,E)-6,10,14-trimethylpentadec-5-en-2-one 122° C. at 2 mbar(R,Z)-6,10,14-trimethylpentadec-5-en-2-one 119° C. at 2 mbar

In a preferred embodiment the distillation is done in the presence of acis/trans isomerization catalyst.

Cis/Trans Isomerization

Cis/trans isomerization catalysts are catalysts which isomerize thecarbon-carbon double bonds. It has been found that for the purpose ofthis invention said cis/trans isomerization catalysing the cis/transisomerization of the double bonds in the 5 and 9 positions isparticularly nitrogen monoxide (NO) or an organic sulphur compound,particularly a polythiol.

Particularly suitable as cis/trans isomerization catalysts arepolythiols of formula (X) or aromatic polythiols

-   -   wherein n1 represents an integer from 1 to 4, particularly 2,    -   and m1 represents an integer from 2 to 8, particularly 3 or 4,        preferably 4;    -   and A represents an aliphatic m1-valent hydrocarbon group of the        molecular weight of between 28 g/mol and 400 g/mol, particularly        between 90 and 150 g/mol.

The polythiols pentaerythritol tetra(mercaptoacetate),trimethylolpropane tris(mercaptoacetate), glycol dimercaptoacetate,pentaerythritol tetra-(3-mercaptopropionate),trimethylolpropanetri-(3-mercaptopropionate)(=2-ethyl-2-(((3-mercaptopropanoyl)oxy)methyl)propane-1,3-diylbis(3-mercaptopropanoate)) and glycol di-(3-mercaptopropionate) havebeen shown to be highly preferred polythiols of formula (X) and are thepreferred polythiols of all the above mentioned polythiols.

Particularly preferred as aromatic polythiols are4,4′-dimercaptobiphenyl or 4,4′-thiodibenzenethiol.

The use of polythiols of formula (X) as cis/trans isomerizationcatalysts is very advantageous in that polythiols have generally verylow vapor pressures (i.e. high boiling points) allowing them to be usedat elevated temperatures, e.g. while distilling the low boiling isomer.Furthermore, the polythiols bear a high density of thiol-functionalitiesper molecular weight, which is very advantageous, in that only littlecatalyst needs to be added.

The use of polythiol as cis/trans isomerization catalysts is veryadvantageous as they allow a very fast isomerization.

Nitrogen monoxide (NO) is a gas and can be introduced to the ketone orketal to be isomerized as such or in the form of a gas mixture,particularly in combination with at least one inert gas, particularlywith nitrogen. In the case a gas mixture is used the amount of nitrogenmonoxide in the gas mixture is preferably in the range of 1-99%,particularly of 5-95%, by weight of the gas mixture. Particularly, inview of corrosion and toxicity, the amount of nitrogen monoxide in thegas mixture is preferably in the range of 10-60%) by weight of the gasmixture.

The use of nitrogen monoxide as cis/trans isomerization catalysts isvery advantageous in that the isomerization catalyst can be removed veryeasily from the ketone or ketal to be isomerized.

Nitrogen monoxide is preferably introduced to the ketone or ketal atatmospheric pressure or up to 1 MPa over-pressure. The over-pressurepreferably amounts to 10 to 300 kPa.

Nitrogen monoxide (NO) or a mixture of nitrogen monoxide (NO) with othergases is preferably introduced in a continuous way by means of a tubeand bubbled through the ketone or ketal to be isomerized.

The use of cis/trans isomerization allows the transformation of a purecis or trans isomer or any mixtures of the isomers to yield athermodynamically equilibrated mixture of the cis and trans isomer.Overall, this enables the separation of the desired isomer bydistillation and transformation (isomerization) of the non-preferredisomer (residual isomer) into the desired isomer.

The distillation can be performed in the presence of the cis/transisomerization catalyst (one-pot isomerization or in-situ isomerization),so that the desired isomer is re-formed continuously and can beseparated by distillation.

Furthermore, the cis/trans isomerization can occur in a separate vesselin which the cis/trans isomerization catalyst is added to the remainderof the distillation. Hence, the residual isomer is isomerized by meansof a cis/trans isomerization catalyst and subsequently added to thecorresponding mixture of isomers provided in steps a) and d),respectively.

The use of the cis/trans isomerization in step b) and/or e) allows ahigh yield in the desired isomer. In preferred cases, it can be achievedthat essentially all of the undesired isomer is overall isomerized tothe desired isomer.

Preferably, particularly in the case where the isomerization catalyst isnot nitrogen monoxide, more preferably in the case of polythiols asisomerization catalysts, the isomerization is undertaken at temperatureshigher than 20° C., particularly at a temperature of between 20° C. andthe boiling point of the desired isomer, particularly between 50° C. andthe boiling point of the desired isomer. The isomerization can occur atambient pressure or at reduced pressure. In case of the one-potisomerization the isomerization is preferably undertaken under reducedpressure.

Particularly for the case of nitrogen monoxide being cis/transisomerization catalyst the isomerization is undertaken at ambient orover pressure.

It further has been observed that in the isomerization with polythiolsaddition of polar solvents such as amides, pyrrolidones, sulfones,sulfoxides, ionic liquids, particularly N,N-dimethylformide (DMF) orN-methyl-2-pyrrolidone (NMP), sulfolane, dimethylsulfoxide (DMSO) and1-butyl-3-methylimidazolium bromide has an accelerating effect on theisomerization.

Therefore, it is preferred that the process of a cis/trans isomerizationis undertaken in the presence of a polar solvent, particularly a polarsolvent which is selected from the group consisting of ionic liquids,particularly 1-butyl-3-methylimidazolium bromide, N,N-dimethylformide(DMF), N-methyl-2-pyrrolidone (NMP), sulfolane and dimethylsulfoxide(DMSO).

More preferred it is that the process of a cis/trans isomerization isundertaken in the presence of a polar solvent, particularly a polarsolvent which is selected from the group consisting of ionic liquids,particularly 1-butyl-3-methylimidazolium bromide, N,N-dimethylformide(DMF), N-methyl-2-pyrrolidone (NMP) and dimethylsulfoxide (DMSO).

The amount of cis/trans isomerization catalyst is preferably between 1and 20% by weight in relation to the amount of the isomers of6,10-dimethylundec-5-en-2-one or of 6,10-dimethylundeca-5,9-dien-2-one,respectively to (R)-6,10,14-trimethylpentadec-5-en-2-one.

Ketal Formation

In a further embodiment before the step c) a step c_(o)) takes place

-   -   c_(o)) forming a ketal of the isomer of        6,10-dimethylundec-5-en-2-one or of        6,10-dimethylundeca-5,9-dien-2-one separated in step b).

Hence, in step c) the ketal of 6,10-dimethylundec-5-en-2-one or of6,10-dimethylundeca-5,9-dien-2-one is asymmetrically hydrogenated andafter the asymmetric hydrogenation the hydrogenated ketal is hydrolysedto the ketone and yielding (R)-6,10-dimethylundecan-2-one.

In a further embodiment before the step f) a step f_(o)) takes place

-   -   f_(o)) forming a ketal of the isomer of        (R)-6,10,14-trimethylpentadec-5-en-2-one separated in step e)

Hence, in step f) the ketal of (R)-6,10,14-trimethylpentadec-5-en-2-oneis asymmetrically hydrogenated and after the asymmetric hydrogenationthe hydrogenated ketal is hydrolysed to the ketone and yielding(6R,10R)-6,10,14-trimethylpentadecan-2-one.

The formation of a ketal from a ketone, per se, is known to the personskilled in the art.

The ketal of an unsaturated ketone can be preferably formed from theabove mentioned unsaturated ketone and an alcohol.

It is known to the person skilled in the art that there are alternativeroutes of synthesis for ketals. In principle, the ketal can also beformed by treating a ketone with ortho-esters or by trans-ketalizationsuch as disclosed for example in Pério et al., Tetrahedron Letters 1997,38 (45), 7867-7870, or in Lorette and Howard, J. Org. Chem. 1960,521-525, the entire content of both is hereby incorporated by reference.

Preferably the ketal is formed from the above mentioned unsaturatedketone and an alcohol.

The alcohol can comprise one or more hydroxyl groups. The alcohol may bea phenolic alcohol or an aliphatic or cycloaliphatic alcohol. Preferablythe alcohol has one or two hydroxyl groups.

In case the alcohol has one hydroxyl group, the alcohol is preferably analcohol which has 1 to 12 carbon atoms. Particularly, the alcohol havingone hydroxyl group is selected from the group consisting of methanol,ethanol, 1-propanol, 2-propanol, 1-butanol, 2-methyl-1-propanol,2-butanol, pentane-1-ol, 3-methylbutane-1-ol, 2-methylbutane-1-ol,2,2-dimethylpropan-1-ol, pentane-3-ol, pentane-2-ol,3-methylbutane-2-ol, 2-methylbutan-2-ol, hexane-1-ol, hexane-2-ol,hexane-3-ol, 2-methyl-1-pentanol, 3-methyl-1-pentanol,4-methyl-1-pentanol, 3-methyl-2-pentanol, 4-methyl-2-pentanol,2-methyl-3-pentanol, 2,2-dimethyl-1-butanol, 2,3-dimethyl-1-butanol,3,3-dimethyl-1-butanol, 3,3-dimethyl-2-butanol, 2-ethyl-1-butanol, andall structural isomers of heptanol, octanol and halogenated C₁-C₈-alkylalcohols, particularly 2,2,2-trifluoroethanol. Particularly suitable areprimary or secondary alcohols. Preferably primary alcohols are used asalcohols with one hydroxyl group. Particularly methanol, ethanol,1-propanol, 2-propanol, 1-butanol, 2-butanol or 2,2,2-trifluoroethanol,preferably methanol, ethanol, 1-propanol, 1-butanol or2,2,2-trifluoroethanol, are used as alcohols with one hydroxyl group.

In another embodiment the alcohol is a diol, hence has two hydroxylgroups. Preferably the diol is selected from the group consisting ofethane-1,2-diol, propane-1,2-diol, propane-1,3-diol, butane-1,4-diol,butane-1,3-diol, butane-1,2-diol, butane-2,3-diol,2-methylpropane-1,2-diol, 2,2-dimethylpropane-1,3-diol,1,2-dimethylpropane-1,3-diol, benzene-1,2-diol andcyclohexane-1,2-diols. From two cyclohexane-1,2-diols the preferredstereoisomer is syn-cyclohexane-1,2-diol (=cis-cyclohexane-1,2-diol).

The two hydroxyl group are in one embodiment bound to two adjacentcarbon atoms, hence these dials are vicinal dials. Vicinal dials form a5 membered ring in a ketal.

Particularly suitable are vicinal dials which are selected from thegroup consisting of ethane-1,2-diol, propane-1,2-diol, butane-1,2-diol,butane-2,3-diol, 2-methylpropane-1,2-diol, benzene-1,2-dial andsyn-cyclohexane-1,2-diol, particularly ethane-1,2-diol.

Other particularly suitable are dials, in which the hydroxyl groups areseparated by 3 carbon atoms, and, hence, form a very stable 6 memberedring in a ketal. Particularly suitable dials of this type arepropane-1,3-diol, butane-1,3-diol, 2-methylpropane-1,3-diol,2-methylbutane-1,3-diol, 2,2-dimethylpropane-1,3-diol,1,2-dimethylpropane-1,3-diol, 3-methylpentane-2,4-dial and2-(hydroxymethyl)-cyclohexanol.

Preferably primary alcohols are used as dials.

The reaction conditions and stoichiometry used for the ketal formationare known to the person skilled in the art.

The preferred ketals have the formula (XI) or (XII)

-   -   wherein a wavy line represents a carbon-carbon bond which is        linked to the adjacent carbon-carbon double bond so as to have        said carbon-carbon double bond either in the Z or in the        E-configuration;    -   and wherein the double bond having dotted lines (        ) in formula represent either a single carbon-carbon bond or a        double carbon-carbon bond;    -   and wherein        represents a stereogenic centre;    -   and wherein    -   Q¹ and Q²        -   stand either individually or both for a C₁-C₁₀ alkyl group            or a halogenated C₁-C₁₀ alkyl group;        -   or form together a C₂-C₆ alkylene group or a C₆-C₈            cycloalkylene group.

Q¹ and Q² stand particularly for

either a linear C₁-C₁₀ alkyl group or fluorinated linear C₁-C₁₀ alkylgroup, preferably a linear C₁-C₄ alkyl group or a —CH₂CF₃ group

or a group of formula

in which Q³, Q⁴, Q⁵ and Q⁶ are independently from each other hydrogenatoms or methyl or ethyl groups.

Particularly Q¹ and Q² stand both for a fluorinated linear C₁-C₁₀ alkylgroup, preferably a linear C₁-C₄ alkyl group or a —CH₂CF₃ group or formtogether the alkylene group CH₂—C(CH₃)₂—CH₂.

Hence the preferred ketals to be asymmetrically hydrogenated areselected from the group consisting of(E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2,5,5-trimethyl-1,3-dioxane,(E)-2-(4,8-dimethylnon-3-en-1-yl)-2,5,5-trimethyl-1,3-dioxane,(E)-2,6-dimethyl-10,10-bis(2,2,2-trifluoroethoxy)undeca-2,6-diene,(E)-6,10-dimethyl-2,2-bis(2,2,2-trifluoroethoxy)undec-5-ene,(Z)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2,5,5-trimethyl-1,3-dioxane,(Z)-2-(4,8-dimethylnon-3-en-1-yl)-2,5,5-trimethyl-1,3-dioxane,(Z)-2,6-dimethyl-10,10-bis(2,2,2-trifluoroethoxy)undeca-2,6-diene,(Z)-6,10-dimethyl-2,2-bis(2,2,2-trifluoroethoxy)undec-5-ene;(E)-2,5,5-trimethyl-2-(4,8,12-trimethyltridec-3-en-1-yl)-1,3-dioxane,(E)-6,10,14-trimethyl-2,2-bis(2,2,2-trifluoroethoxy)pentadec-5-ene,(Z)-2,5,5-trimethyl-2-(4,8,12-trimethyltridec-3-en-1-yl)-1,3-dioxane,and (Z)-6,10,14-trimethyl-2,2-bis(2,2,2-trifluoroethoxy)pentadec-5-ene;(R,E)-2,5,5-trimethyl-2-(4,8,12-trimethyltridec-3-en-1-yl)-1,3-dioxane,(R,E)-6,10,14-trimethyl-2,2-bis(2,2,2-trifluoroethoxy)pentadec-5-ene;(R,Z)-2,5,5-trimethyl-2-(4,8,12-trimethyltridec-3-en-1-yl)-1,3-dioxaneand(R,Z)-6,10,14-trimethyl-2,2-bis(2,2,2-trifluoroethoxy)pentadec-5-ene.

The hydrolysis of the hydrogenated ketal to the corresponding ketone isknown to the person skilled in the art. Particularly suitable is thehydrolysis by means of an acid and isolation of the ketone formed,particularly by means of extraction.

Asymmetric Hydrogenation

Steps c) and f) involve asymmetric hydrogenations by molecular hydrogenin the presence of a chiral iridium complex.

Chiral iridium complexes are compounds having organic ligands beingcoordinated to a central iridium atom. The chirality of chiral iridiumcomplexes is due to either the chirality of the ligands or the spacialarrangements of the ligands. This concept of chirality is well knownfrom complex chemistry. Ligands can be monodentate or polydentate.Preferably, the ligands bound to the iridium central atom are chelatingligands. For the present invention, it has been shown that particularlychiral iridium complexes having an organic ligand bearing a stereogeniccentre are very suitable.

It is preferred that the chiral iridium complex is bound to a chelatingorganic ligand having N and P as coordinating atoms and to either twoolefins or to a diene having two carbon-carbon double bonds, and that,hence, the chiral iridium complex has preferably the following formula(III-0)

whereinP-Q-N stands for a chelating organic ligand comprising a stereogeniccentre or has planar or axial chirality and has a nitrogen andphosphorous atom as binding site to the iridium centre of the complex;Y¹, Y², Y³ and Y⁴ are independently from each other hydrogen atoms,C₁₋₁₂-alkyl, C₅₋₁₀-cycloalkyl, or aromatic group; or at least two ofthem form together at least a two-valent bridged group of at least 2carbon atoms; with the proviso that Y¹, Y², Y³ and Y⁴ are not allhydrogen atoms; andY^(⊖) is an anion, particularly selected from the group consisting ofhalide, PF₆ ⁻, SbF₆ ⁻, tetra(3,5-bis(trifluoromethyl)phenyl)borate(BAr_(F) ⁻), BF₄ ⁻, perfluorinated sulfonates, preferably F₃C—SO₃ ⁻ orF₉C₄—SO₃ ⁻; ClO₄ ⁻, Al(OC₆F₅)₄ ⁻, Al(OC(CF₃)₃)₄ ⁻, N(SO₂CF₃)₂⁻N(SO₂C₄F₉)₂ ⁻ and B(C₆F₅)₄ ⁻.

The nitrogen and the phosphorous atom are preferably separated by 2 to5, preferably 3, atoms in the chemical formula of the ligand P-Q-N.

The chelating organic ligand P-Q-N is preferably selected from theformulae (III-N1), (III-N2), (III-N3), (III-N4), (III-N5), (III-N6),(III-N7), (III-N8) and (III-N9)

wherein G¹ represents either a C₁-C₄-alkyl, C₅₋₇-cycloalkyl, adamantyl,phenyl (optionally substituted with one to three C₁₋₅-alkyl,C₁₋₄-alkoxy, C₁₋₄-perfluoroalkyl groups and/or one to five halogenatoms)), benzyl, 1-naphthyl, 2-naphthyl, 2-furyl group;

G², G³ and G⁴ represent independently from each other hydrogen atoms ora C₁-C₄-alkyl, C₅₋₇-cycloalkyl, adamantyl, phenyl (optionallysubstituted with one to three C₁₋₅-, C₁₋₄-alkoxy, C₁₋₄-perfluoroalkylgroups and/or one to five halogen atoms)), benzyl, 1-naphthyl,2-naphthyl, 2-furyl group;

X¹ and X² are independently from each other hydrogen atoms, C₁₋₄-alkyl,C₅₋₇-cycloalkyl, adamantyl, phenyl (optionally substituted with one tothree C₁₋₅-alkyl, C₁₋₄-alkoxy, C₁₋₄-perfluoroalkyl groups and/or one tofive halogen atoms)), benzyl, 1-naphthyl, 2-naphthyl, 2-furyl orferrocenyl;

Ph stands for phenyl;

n is 1 or 2 or 3, preferred 1 or 2;

and R¹, Z¹ and Z² are as defined later for formula (III)

In case Y¹ and Y² and/or Y³ and Y⁴ form an olefin of the formula Y¹-═-Y²and/or of the Formula Y³-═-Y⁴, this olefin is or these olefins arepreferably selected from the group consisting of ethene, prop-1-ene,2-methylprop-1-ene, 2-methyl-but-2-ene, 2,3-dimethylbut-2-ene,(Z)-cyclooctene, cyclohexene, cycloheptene, cyclopentene and norbornene.

In case Y¹, Y², Y³ and Y⁴ are forming a diene, it is either cyclic(double bond in a cycle) or acyclic (double bond not in a cycle).

The two carbon-carbon double bonds of the diene are preferably linked bytwo carbon bonds, i.e. the dienes preferably comprise the substructureC═C—C—C—C═C.

Examples of preferred acylic dienes are hexa-1,5-diene, hepta-1,5-diene,octa-1,5-diene, octa-2,6-diene, 2,4-dialkyl-2,7-octadiene,3,6-dialkylocta-2,6-diene, 1,2-divinylcyclohexane and 1,3-butadiene.

Examples for cyclic dienes are cycloocta-1,5-diene, cyclohexa-1,4-diene,cyclohexa-1,3-diene, 3,4,7,8-tetraalkylcycloocta-1,5-diene,3,4,7-trialkylcycloocta-1,5-diene, 3,4-di-alkylcycloocta-1,5-diene,3,7-di-alkylcycloocta-1,5-diene, 3,8-di-alkylcycloocta-1,5-diene,3-alkylcycloocta-1,5-diene; norbornadiene, 1-alkylnorbornadiene,2-alkylnorbornadiene, 7-alkylnorbornadiene, dicyclopentadiene,cyclopentadiene and (1s,4s)-bicyclo[2.2.2]octa-2,5-diene.

Preferred diene is cycloocta-1,5-diene.

A highly preferred class of chiral iridium complexes are chiral iridiumcomplexes of formula (III)

-   -   wherein    -   n is 1 or 2 or 3, preferred 1 or 2;    -   X¹ and X² are independently from each other hydrogen atoms,        C₁₋₄-alkyl, C₅₋₇-cycloalkyl, adamantyl, phenyl (optionally        substituted with one to three C₁₋₅-, C₁₋₄-alkoxy,        C₁₋₄-perfluoroalkyl groups and/or one to five halogen atoms)),        benzyl, 1-naphthyl, 2-naphthyl, 2-furyl or ferrocenyl;    -   Z¹ and Z² are independently from each other hydrogen atoms,        C₁₋₅-alkyl or C₁₋₅-alkoxy groups;    -   or Z¹ and Z² stand together for a bridging group forming a 5 to        6 membered ring;    -   Y^(⊖) is an anion, particularly selected from the group        consisting of halide, PF₆ ⁻, SbF₆ ⁻,        tetra(3,5-bis(trifluoromethyl)phenyl)borate (BAr_(F) ⁻), BF₄ ⁻,        perfluorinated sulfonates, preferably F₃C—SO₃ ⁻ or F₉C₄—SO₃ ⁻;        ClO₄ ⁻, Al(OC₆F₅)₄ ⁻, Al(OC(CF₃)₃)₄ ⁻, N(SO₂CF₃)₂ ⁻N(SO₂C₄F₉)₂ ⁻        and B(C₆F₅)₄ ⁻;    -   R¹ represents either phenyl or o-tolyl or m-tolyl or p-tolyl or        a group of formula (IVa) or (IVb) or (IVc)

-   -   -   wherein R² and R³ represent either both H or a C₁-C₄-alkyl            group or a halogenated C₁-C₄-alkyl group or represent a            divalent group forming together a 6-membered cycloaliphatic            or an aromatic ring which optionally is substituted by            halogen atoms or by C₁-C₄-alkyl groups or by C₁-C₄-alkoxy            groups        -   R⁴ and R⁵ represent either both H or a C₁-C₄-alkyl group or            a halogenated C₁-C₄-alkyl group or a divalent group forming            together a 6-membered cycloaliphatic or an aromatic ring            which optionally is substituted by halogen atoms or by            C₁-C₄-alkyl groups or by C₁-C₄-alkoxy groups;        -   R⁶ and R⁷ and R⁸ represent each a C₁-C₄-alkyl group or a            halogenated C₁-C₄-alkyl group;        -   R⁹ and R¹⁹ represent either both H or a C₁-C₄-alkyl group or            a halogenated C₁-C₄-alkyl group or a divalent group forming            together a 6-membered cycloaliphatic or an aromatic ring            which optionally is substituted by halogen atoms or by            C₁-C₄-alkyl groups or by C₁-C₄-alkoxy groups;

    -   and wherein * represents a stereogenic centre of the complex of        formula (III).

The complex of formula (III) is neutral, i.e. the complex consists of acomplex cation of formula (III′) and anion Y as defined before.

The person skilled in the art knows that anions and cations may bedissociated.

X¹ and/or X² represent preferably hydrogen atoms, methyl, ethyl,n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl,iso-pentyl, neopentyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantly,phenyl, benzyl, o-tolyl, m-tolyl, p-tolyl, 4-methoxyphenyl,4-trifluoromethylphenyl, 3,5-di-tert-butylphenyl, 3,5-dimethoxyphenyl,1-naphthyl, naphthyl, 2-furyl, ferrocenyl or a phenyl group which issubstituted with one to five halogen atoms.

In case of X¹ and/or X² representing phenyl groups which are substitutedwith one to five halogen atoms, the phenyl groups substituted byfluorine atoms are particularly useful, i.e. C₆H₄F, C₆H₃F₂, C₆H₂F₃,C₆HF₄ or C₆F₅.

In case of X¹ and/or X² representing phenyl groups which are substitutedwith one to three C₁₋₄-alkyl, the phenyl groups substituted by methylgroup(s) are particularly useful, particularly ortho-tolyl andpara-tolyl.

Preferably both X¹ and X² represent the same substituent.

Most preferred both X¹ and X² are phenyl or ortho-tolyl groups.

It is preferred that the C₁-C₄-alkyl or alkoxy groups used in thedefinition of R², R³, R⁴, R⁵ R⁶, R⁷, R⁸, R⁹ and R¹⁹ above are primary orsecondary, preferably primary, alkyl or alkoxy groups.

A particularly suited substituent R¹ of formula (IVa) is the 9-anthrylor 1-naphthyl group.

A further particularly suited substituent R¹ of formula (IVb) is themesityl group.

A further particularly suited substituent R¹ of formula (IVc) is the2-naphthyl group.

Preferably R¹ is represented by phenyl (abbreviated as “Ph”) or formula(IV-1) or (IV-2) or (IV-3), particularly (IV-1) or (IV-3).

It has been found that the most preferred substituent R¹ is either9-anthryl or phenyl.

The preferred chiral iridium complexes of formula (III) are thecomplexes of formulae (III-A), (III-B), (III-C), (III-D), (III-E) and(III-F).

Most preferred as chiral iridium complexes of formula (III) are thecomplexes of formulae (III-C) and (III-D) and (III-F), particularly theone of formula (III-C) or (III-F).

The chiral iridium complexes of formula (III) can be synthesizedaccordingly as described in detail in Chem. Sci., 2010, 1, 72-78 whoseentire content is hereby incorporated by reference.

The iridium complex of formula (III) is chiral. The chirality at saidchiral centre marked by the asterisk is either S or R. i.e. there existtwo enantiomers (IIIa) and (IIIb) of the chiral complex of formula(III):

The individual enantiomers of the complex of formula (III) could beprincipally separated after the complexation step from a racemicmixture. However, as Chem. Sci., 2010, 1, 72-78 discloses, the synthesisof the complex of formula (III) comprises a reaction involving anon-racemic chiral alcohol. As it is known that the further reactionsteps do not modify the chirality of the complex its isomeric purity(S:R-ratio) is governed therefore by the enantiomeric purity of saidalcohol. As said corresponding alcohol can be obtained in a R/S ratio ofmore than 99% resp. lower than 1%, the complex of formula (III) can beobtained in extremely high enantiomeric purities, particularly in a R/Sratio of more than 99% resp. lower than 1%.

The chiral iridium complex is preferably used in an excess of oneenantiomer.

Particularly, it is preferred that the ratio of the molar amounts of theindividual enantiomers R:S of the chiral iridium complex of formula(III) is more than 90:10 or less than 10:90, preferably in the range of100:0 to 98:2 or 0:100 to 2:98. Most preferred is that this ratio isabout 100:0 resp. about 0:100. The ultimately preferred ratio is 100:0resp. 0:100.

In one embodiment the stereogenic centre indicated by * has theR-configuration.

In another embodiment the stereogenic centre indicated by * has theS-configuration.

The hydrogenating agent is molecular hydrogen (H₂).

The amount of chiral iridium complex is preferably from about 0.0001 toabout 5 mol %, preferably from about 0.001 to about 2 mol %, morepreferably from about 0.01 to about 1 mol %, based on the amount of theketone resp. ketal.

The hydrogenation can be carried out in substance or in an inertcarrier, particularly in an inert solvent, or a mixture of inertsolvents. The hydrogenation is preferred carried out in substance(neat).

Preferred suitable solvents are halogenated hydrocarbons, hydrocarbons,carbonates, ethers and halogenated alcohols.

Particularly preferred solvents are hydrocarbons, fluorinated alcoholsand halogenated hydrocarbons, particularly halogenated aliphatichydrocarbons.

Preferred examples of hydrocarbons are hexane, heptane, toluene, xyleneand benzene, particularly toluene and heptane.

Preferred ethers are dialkylethers. Particularly useful ethers aredialklyethers with less than 8 carbon atoms. Most preferred ether ismethyl tert.-butyl ether (CH₃—O—C(CH₃)₃).

Preferred halogenated alcohols are fluorinated alcohols. A particularlypreferred fluorinated alcohol is 2,2,2-trifluoroethanol.

One preferred group of halogenated hydrocarbon are halogenated aromaticcompounds, particularly chlorobenzene.

Preferred examples of halogenated aliphatic hydrocarbons are mono- orpolyhalogenated linear or branched or cyclic C₁- to C₁₅-alkanes.Especially preferred examples are mono- or polychlorinated or-brominated linear or branched or cyclic C₁- to C₁₅-alkanes. Morepreferred are mono- or polychlorinated linear or branched or cyclic C₁-to C₁₅-alkanes. Most preferred are dichloromethane, 1,2-dichloroethane,1,1,1-trichloroethane, chloroform, and methylene bromide.

The most preferred solvent for the hydrogenation is dichloromethane.

The amount of solvent used is not very critical. However, it has beenshown that the concentration of the ketone or ketal to be hydrogenatedis preferably between 0.05 and 1 M, particularly between 0.2 and 0.7 M.

The hydrogenation reaction is conveniently carried out at an absolutepressure of molecular hydrogen from about 1 to about 100 bar, preferablyat an absolute pressure of molecular hydrogen from about 20 to about 75bar. The reaction temperature is conveniently between about 0 to about100° C., preferably between about 10 to about 60° C.

The sequence of addition of the reactants and solvent is not critical.

The technique and apparatus suitable for the hydrogenation isprincipally known to the person skilled in the art.

By the asymmetric hydrogenation a prochiral carbon-carbon double bond ishydrogenated to form a chiral stereogenic centre at one or both of thecarbon atoms.

In step c) either 6,10-dimethylundec-5-en-2-one or6,10-dimethylundeca-5,9-dien-2-one, or a ketal of6,10-dimethylundec-5-en-2-one or a ketal of6,10-dimethylundeca-5,9-dien-2-one is asymmetrically hydrogenated.

In step f) either 6,10,14-trimethylpentadec-5-en-2-one or a ketal of6,10,14-trimethylpentadec-5-en-2-one is hydrogenated.

In case a ketal is asymmetrically hydrogenated, after the asymmetrichydrogenation the asymmetrically hydrogenated ketal has preferably theformula (XV) or (XVI).

wherein

represents a stereogenic centre;

and wherein Q¹ and Q² are as defined for formula (XI) and (XII).

Hence the preferred ketals which have been asymmetrically hydrogenatedare preferably selected from the group consisting of2-(4,8-dimethylnonyl)-2,5,5-trimethyl-1,3-dioxane,6,10-dimethyl-2,2-bis(2,2,2-trifluoroethoxy)undecane,2,5,5-trimethyl-2-(4,8,12-trimethyltridecyl)-1,3-dioxane,6,10,14-trimethyl-2,2-bis(2,2,2-trifluoroethoxy)pentadecane;

(R)-2-(4,8-dimethylnonyl)-2,5,5-trimethyl-1,3-dioxane,(R)-6,10-dimethyl-2,2-bis(2,2,2-trifluoroethoxy)undecane,2,5,5-trimethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)-1,3-dioxane and(6R,10R)-6,10,14-trimethyl-2,2-bis(2,2,2-trifluoroethoxy)-pentadecane.

When these ketals are hydrolysed into the corresponding ketone, theyyield 6,10-dimethylundecan-2-one or 6,10,14-trimethylpentadecan-2-one,or (R)-6,10-dimethylundecan-2-one or(6R,10R)-6,10,14-trimethylpentadecan-2-one, respectively.

Despite the fact that the asymmetric hydrogenation of6,10-dimethylundec-5-en-2-one, 6,10-dimethylundeca-5,9-dien-2-one and(R)-6,10,14-trimethylpentadec-5-en-2-one by means of molecular hydrogenin the presence of a chiral iridium complex, particularly those offormula (III), is already rather fast and efficient and shows highconversion rates as well as excellent selectivities, it has beenobserved that the asymmetric hydrogenation can even be improved whenketals of the corresponding ketones are asymmetrically hydrogenated.

It has been observed that the chiral iridium complex of a specificchirality (R or S) converts the starting material into a product bearinga specific stereogenic centre, which is formed as a result of theasymmetric hydrogenation.

As is in the present invention it is desired to produce products bearinga stereocentre with R-configuration by asymmetric hydrogenation i.e.(R)-6,10-dimethylundecan-2-one in step c), and(6R,10R)-6,10,14-trimethylpentadecan-2-one in step f), respectively, thechirality of the chiral iridium complex needs to be selected dependingon whether the olefin isomers being separated in step c) and step e),respectively, have the Z- or E-configuration.

It has been shown that when chiral iridium complexes of formula (III)having the S-configuration at the stereogenic centre indicated by * areused for the hydrogenation of E-isomers, i.e.(E)-6,10-dimethylundec-5-en-2-one and(R,E)-6,10,14-trimethylpentadec-5-en-2-one, respectively, thecorresponding products, i.e. (R)-6,10-dimethylundecan-2-one in step c),and (6R,10R)-6,10,14-trimethylpentadecan-2-one in step f), are obtainedbearing the R-configuration at the newly formed stereogenic centre.Correspondingly, the hydrogenation of Z-isomers, i.e.(Z)-6,10-dimethylundec-5-en-2-one and(R,Z)-6,10,14-trimethylpentadec-5-en-2-one, respectively, in thepresence of the chiral iridium complex of formula (III) having theR-configuration at the stereogenic centre indicated by * furnishes thesame products, i.e. (R)-6,10-dimethylundecan-2-one in step c), and(6R,10R)-6,10,14-trimethylpentadecan-2-one in step f), are obtainedbearing the R-configuration at the newly formed stereogenic centre

Surprisingly, it has been found that this finding is independent fromwhether a ketone or a ketal is used in step c) or f).

Therefore, the chiral iridium complex of formula (III) used in step c)and/or f) for the asymmetric hydrogenation preferably has the

-   -   S-configuration at the stereogenic centre indicated by * in case        (E)-6,10-dimethylundec-5-en-2-one,        (E)-6,10-dimethylundeca-5,9-dien-2-one, or ketals thereof, or        (R,E)-6,10,14-trimethylpentadec-5-en-2-one, or a ketal thereof,        are to be hydrogenated;

or has the

-   -   R-configuration at the stereogenic centre indicated by * in case        (Z)-6,10-dimethylundec-5-en-2-one,        (Z)-6,10-dimethylundeca-5,9-dien-2-one, or ketals thereof, or        (R,Z)-6,10,14-trimethylpentadec-5-en-2-one, or a ketal thereof,        are to be hydrogenated.        Additives

In a preferred embodiment of the invention the asymmetric hydrogenationin step c) and/or step f) takes place in the presence of an additivewhich is selected from the group consisting of organic sulfonic acids,transition metal salts of organic sulfonic acids, metal alkoxides,aluminoxanes, alkyl aluminoxanes and B(R)_((3-v))(OZ)_(v); wherein vstands for 0, 1, 2 or 3 and R stands for F, a C₁₋₆-alkyl, a halogenatedC₁₋₆-alkyl, an aryl or halogenated aryl group; and Z stands aC₁₋₆-alkyl, a halogenated C₁₋₆-alkyl, an aryl or halogenated aryl group.

Particularly suitable additives are selected from the group consistingof triflic acid, alkyl aluminoxanes, particularly methyl aluminoxane,ethyl aluminoxane, tetra alkoxy titanates. B(R)_((3-v))(OZ)_(v);particularly tri-isopropylborate and triethylborane and BF₃, preferablyin the form of a BF₃ etherate.

Particularly useful as the transition metal salts of organic sulfonicacids are scandium, indium, yttrium and zirconium salts of organicsulfonic acids.

Metal alkoxides are known to the person skilled in the art. This termparticularly relates to the alkoxides of the elements of the group 4 and13 of the periodic system. It is also known to the person skilled in theart that the metal alkoxides often do not form well-defined structures.Characteristically, metal alkoxides have hydrocarbyl group bound by anoxygen atom to a metal centre. A metal alkoxide may also have differentmetal centres which are bridged by oxygen or oxygen containing groups,such as for example (polynuclear) aluminium oxoalkoxides.

Particularly useful as metal alkoxides are titanium alkoxides (alsobeing called alkoxy titanates) zirconium alkoxides (also being calledalkoxy zirconates) or aluminium alkoxides.

A particularly preferred class of metal alkoxide is of the type ofpolynuclear aluminium oxoalkoxides such as disclosed in J. Chem. Soc.,Dalton Trans., 2002, 259-266 or in Organometallics 1993, 12, 2429-2431.

Alkyl aluminoxanes, are known products which are particularly useful asco-catalysts for olefin polymerizations of the Ziegler-Natta type. Theyare prepared by controlled hydrolysis of trialkylaluminium compound,particularly trimethylaluminium or triethylaluminium. The hydrolysis canbe achieved for example by hydrated metal salts (metal salts containingcrystal water).

Preferably the additive is selected from the group consisting of triflicacid, alkyl aluminoxanes, particularly methyl aluminoxane, ethylaluminoxane, tetra alkoxy titanates. B(R)_((3-v))(OZ)_(v); particularlytri-isopropylborate and triethylborane and BF₃, preferably in the formof a BF₃ etherate.

More preferred are triflic acid, alkyl aluminoxanes, particularly methylaluminoxane, ethyl aluminoxane, tetra alkoxy titanates,B(R)_((3-v))(OZ)_(v); particularly tri-isopropylborate andtriethylborane.

Especially good results have been obtained by an additive with has beenobtained from trimethylaluminoxane and 2,2,2-trifluoroethanol or fromtrialkylaluminium and 2,2,2-trifluoroethanol.

It has been found that the quality and speed of the asymmetrichydrogenation using molecular hydrogen in the presence of a chiraliridium complex is enhanced significantly when the above mentionedadditives are used.

It has been further observed that, most significantly, the efficiency ofthe asymmetric hydrogenation is maximized when the above mentionedadditives are used with the corresponding ketal of the ketones to beasymmetrically hydrogenated, i.e. ketals of6,10-dimethylundec-5-en-2-one, 6,10-dimethylundeca-5,9-dien-2-one and(R)-6,10,14-trimethylpentadec-5-en-2-one.

The increased efficiency has the effect that the amount of chiraliridium complex can be remarkably lowered by using an ketal of6,10-dimethylundec-5-en-2-one, 6,10-dimethylundeca-5,9-dien-2-one or(R)-6,10,14-trimethylpentadec-5-en-2-one. and/or addition of thementioned additive(s), particularly in the combination with fluorinatedalcohols, particularly 2,2,2-trifluoroethanol, to achieve a given yieldand stereospecific hydrogenation in the asymmetric hydrogenation ascompared to the corresponding asymmetric hydrogenation of6,10-dimethylundec-5-en-2-one, 6,10-dimethylundeca-5,9-dien-2-one and(R)-6,10,14-trimethylpentadec-5-en-2-one as such.

When the process comprises steps of cis/trans isomerization, asdiscussed above in detail, the process of invention is extremelyinteresting because for an optimal use of all starting material, it isnot necessary to set up two parallel product lines for the separateasymmetric hydrogenation of each isomer using hydrogenation complexes ofopposite chirality. Therefore, the in-situ isomerization, as discussedabove, is much preferred.

Chemical Transformation

In step d) (R)-6,10-dimethylundecan-2-one is chemically transformed to amixture of (R,E)-6,10,14-trimethylpentadec-5-en-2-one and(R,Z)-6,10,14-trimethylpentadec-5-en-2-one;

This chemical transformation can be done in different ways.

In a preferred method the chemical transformation of(R)-6,10-dimethylundecan-2-one to a mixture of(R,E)-6,10,14-trimethylpentadec-5-en-2-one and(R,Z)-6,10,14-trimethylpentadec-5-en-2-one in step d) is done by thesteps

either

-   -   d1) ethynylation of (R)-6,10-dimethylundecan-2-one using ethyne        in the presence of a basic substance to yield        (7R)-3,7,11-trimethyldodec-1-yn-3-ol;    -   d2) hydrogenation of (7R)-3,7,11-trimethyldodec-1-yn-3-ol with        molecular hydrogen in the presence of a Lindlar catalyst to        yield (7R)-3,7,11-trimethyldodec-1-en-3-ol;

or

-   -   d1′) vinylation of (R)-6,10-dimethylundecan-2-one by addition of        a vinyl Grignard reagent to yield        (7R)-3,7,11-trimethyldodec-1-en-3-ol;

followed by

either

-   -   d3) reacting (7R)-3,7,11-trimethyldodec-1-en-3-ol with        2-methoxyprop-1-ene to yield a mixture of        (R,E)-6,10,14-trimethylpentadec-5-en-2-one and        (R,Z)-6,10,14-trimethylpentadec-5-en-2-one;

or

-   -   d3′) reacting (7R)-3,7,11-trimethyldodec-1-en-3-ol with an alkyl        acetoacetate or diketene in the presence of a base and/or an        acid to yield a mixture of        (R,E)-6,10,14-trimethylpentadec-5-en-2-one and        (R,Z)-6,10,14-trimethylpentadec-5-en-2-one.

Details for the reaction type and conditions of the variant using stepsd1) is disclosed in EP 1 532 092 B1, particularly in example 2, or WO2003/029175 A1 (using a basic anion exchange resin), the entire contentof which is hereby incorporated by reference. The hydrogenation withmolecular hydrogen in the presence of a Lindlar catalyst in step d2) isknown to the person skilled in the art. For example A. Ofner et al,Helv. Chin. Acta 1959, 42, 2577-2584 disclose the combination of stepsd1) and d2) the entire content of which is hereby incorporated byreference.

U.S. Pat. No. 4,028,385 for example discloses details for the reactiontype and conditions of the variant using step d1′) as well as also forsteps d1) and d2), the entire content of which is hereby incorporated byreference.

Details for the reaction type and conditions of the variant using stepd3), which is a Saucy-Marbet reaction, are disclosed for example in DE1193490 and DE 196 49 564 A1, the entire content of both documents ishereby incorporated by reference.

Details for the reaction type and conditions of the first variant instep d3′), which is a Carroll rearrangement, are disclosed for examplein chapter 8 “The Carroll Rearrangement” in Hatcher et al., The ClaisenRearrangement; Hiersemann, M.; Nubbemeyer, U., Eds.; Wiley-VCH VerlagGmbH & Co. KGaA, 2007; 397-430, the entire content of both documents ishereby incorporated by reference. In the Carroll rearrangement thereaction occurs with an alkyl acetoacetate, preferably methylacetoacetate or ethyl acetoacetate, in the presence of a base,preferably an alkali acetate such as sodium acetate.

The reaction type and conditions of the second variant in step d3′) aredisclosed for example in U.S. Pat. No. 2,795,617 or in W. Kimel et al.,J. Org. Chem. 1957, 22, 1611-1618, the entire content of both documentsis hereby incorporated by reference. The reaction preferably occurs withdiketene in the presence of preferably pyridine and acetic acid resp. inthe presence of an alkoxide.

As mentioned earlier, (6R,10R)-6,10,14-trimethylpentadecan-2-one is animportant intermediate and is particularly useful for the synthesis of(R,R)-isophytol, (2-ambo)-α-tocopherol or of (2R,4′R,8′R)-α-tocopherol.

Therefore, in a further aspect the invention relates to a process ofmanufacturing (R,R)-isophytol((3RS,7R,11R)-3,7,11,15-tetramethylhexadec-1-en-3-ol) which comprises

-   -   the process of manufacturing        (6R,10R)-6,10,14-trimethylpentadecan-2-one as described above in        detail;

followed by the steps

either

-   -   g) ethynylation of (6R,10R)-6,10,14-trimethylpentadecan-2-one        using ethyne in the presence of a base to yield        (7R,11R)-3,7,11,15-tetramethylhexadec-1-yn-3-ol;    -   h) hydrogenation of        (7R,11R)-3,7,11,15-tetramethylhexadec-1-yn-3-ol with molecular        hydrogen in the presence of a Lindlar catalyst to yield        (R,R)-isophytol;    -   or    -   h′) vinylation of (6R,10R)-6,10,14-trimethylpentadecan-2-one by        addition of a vinyl Grignard reagent to yield (R,R)-isophytol.

The conditions for steps g) and h) and h′) correspond to the onesdescribed for the analogous steps d1) and d2) and d1′) in step d).

In a further aspect the invention relates to a process of manufacturingcompound of formula (V) comprising

-   -   the process of manufacturing        (6R,10R)-6,10,14-trimethylpentadecan-2-one as described above in        detail;

followed by the steps

either

-   -   g) ethynylation of (6R,10R)-6,10,14-trimethylpentadecan-2-one        using ethyne in the presence of a basic substance to yield        (7R,11R)-3,7,11,15-tetramethylhexadec-1-yn-3-ol;    -   h) hydrogenation of        (7R,11R)-3,7,11,15-tetramethylhexadec-1-yn-3-ol with molecular        hydrogen in the presence of a Lindlar catalyst to yield        (R,R)-isophytol;    -   or    -   h′) vinylation of (6R,10R)-6,10,14-trimethylpentadecan-2-one by        addition of a vinyl Grignard reagent to yield (R,R)-isophytol;

followed by the steps

-   -   m) condensing (R,R)-isophytol with compound of formula (VI) to        yield compound of formula (V) being an isomeric mixture in view        of the chirality at the centre indicated by #;

The conditions for steps g) and h) and h′) correspond to the onesdescribed for the analogous steps d1) and d2) and d1′) in step d).

The condensation reaction of (R,R)-isophytol and compound of formula(VI), described as step m), is known by the person skilled in the art.For this condensation a series of catalysts may be used such asZnCl₂/mineral acid, BF₃/AlCl₃, Fe/HCl, trifluoroacetic acid or boricacid/carboxylic acid as well as indium(III) or scandium(III) salts asdisclosed in WO 2005/121115 A1. Furthermore, suitable catalysts areheteropoly acids, particularly 12-tungstophosphoric acid or12-tungstosilicic acid such as disclosed in EP 0 970 953 A1.

The compounds of formula (V) represent (2-ambo)-α-tocopherol, i.e. amixture of the corresponding (2R,4′R,8′R)-α-tocopherol and(2S,4′R,8′R)-α-tocopherol).

In a further aspect the invention relates to a process of manufacturingcompound of formula (V-A) comprising

-   -   the process of manufacturing        (6R,10R)-6,10,14-trimethylpentadecan-2-one as described above in        detail;

followed by the steps

either

-   -   g) ethynylation of (6R,10R)-6,10,14-trimethylpentadecan-2-one        using ethyne in the presence of a basic substance to yield        (7R,11R)-3,7,11,15-tetramethylhexadec-1-yn-3-ol;    -   h) hydrogenation of        (7R,11R)-3,7,11,15-tetramethylhexadec-1-yn-3-ol with molecular        hydrogen in the presence of a Lindlar catalyst to yield        (R,R)-isophytol;    -   or    -   h′) vinylation of (6R,10R)-6,10,14-trimethylpentadecan-2-one by        addition of a vinyl Grignard reagent to yield (R,R)-isophytol;

followed by the steps

-   -   m) condensing (R,R)-isophytol with compound of formula (VI) to        yield compound of formula (V) being an isomeric mixture in view        of the chirality at the centre indicated by #;

wherein # represents a stereogenic centre;

and

-   -   n) isolating compound of formula (V-A) from the isomeric mixture        of formula (V)

This process of manufacturing compound of formula (V-A) is the same asthe process of manufacturing compound of formula (V) except for anadditional step n).

The isolation of a (2R,4′R,8′R)-α-tocopherol from the corresponding(2-ambo)-α-tocopherol can be achieved by chromatographic separation bymeans of a chiral phase, particularly as described in WO2012/152779 A1.It is also preferred to enhance the yield in (2R,4′R,8′R)-α-tocopherolby means of epimerization of fractions enriched in(2S,4′R,8′R)-α-tocopherol as disclosed as step c) in WO2012/152779 A1.The entire content of WO2012/152779 A1 is hereby included by reference.

The substances selected from the group(E)-6,10-dimethylundec-5-en-2-one, (Z)-6,10-dimethylundec-5-en-2-one,(E)-6,10-dimethylundeca-5,9-dien-2-one,(Z)-6,10-dimethylundeca-5,9-dien-2-one, (R)-6,10-dimethylundecan-2-one;

ketals of (E)-6,10-dimethylundec-5-en-2-one, ketals of(Z)-6,10-dimethylundec-5-en-2-one, ketals of(E)-6,10-dimethylundeca-5,9-dien-2-one, ketals of(Z)-6,10-dimethylundeca-5,9-dien-2-one;(R,E)-6,10,14-trimethylpentadec-5-en-2-one,(R,Z)-6,10,14-trimethylpentadec-5-en-2-one, ketals of(R,E)-6,10,14-trimethylpentadec-5-en-2-one, ketals of(R,Z)-6,10,14-trimethylpentadec-5-en-2-one,(6R,10R)-6,10,14-trimethylpentadecan-2-one, ketals of(6R,10R)-6,10,14-trimethylpentadecan-2-one,(7R)-3,7,11-trimethyldodec-1-yn-3-ol,(7R)-3,7,11-trimethyldodec-1-en-3-ol and (R,R)-isophytol are importantintermediates for the synthesis of tocopherols, vitamin K1, as well asfor flavours and fragrances or for pharmaceutical products. The majorityof them have a typical odour which makes them very attractive to be usedas ingredients in products of the industry of flavours and fragrancessuch as in perfumes.

In a further aspect, the invention relates to a composition comprising

-   -   at least one ketal of formula (XI) or (XII) and    -   at least one chiral iridium complex.

The ketal of formula (XI) or (XII) and the chiral iridium complex, theirratios and as well their preferred embodiments, properties and effectshave been discussed in this documents already in great detail.

In a final aspect, the invention relates to ketals of formula (XX-A) or(XX-B) or (XX-C) or (XX-D)

-   -   wherein the double bond having dotted lines (        ) n the above formulae represents either a single carbon-carbon        bond or a double carbon-carbon bond; and    -   wherein a wavy line represents a carbon-carbon bond which is        linked to an adjacent single carbon bond (        representing        ) or to an adjacent carbon-carbon double bond (        representing        ) so as to have said carbon-carbon double bond either in the Z        or in the E-configuration.

Most preferred are the ketals of formulae (XX-B) and (XX-D).

The preferred ketals are being selected from the group consisting of(E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2,5,5-trimethyl-1,3-dioxane,(E)-2-(4,8-dimethylnon-3-en-1-yl)-2,5,5-trimethyl-1,3-dioxane,(E)-2,6-dimethyl-10,10-bis(2,2,2-tri-fluoroethoxy)undeca-2,6-diene,(E)-6,10-dimethyl-2,2-bis(2,2,2-trifluoroethoxy)undec-5-ene,(Z)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2,5,5-trimethyl-1,3-dioxane,(Z)-2-(4,8-dimethylnon-3-en-1-yl)-2,5,5-trimethyl-1,3-dioxane,(Z)-2,6-dimethyl-10,10-bis(2,2,2-trifluoroethoxy)undeca-2,6-diene,(Z)-6,10-dimethyl-2,2-bis(2,2,2-tri-fluoroethoxy)undec-5-ene;(E)-2,5,5-trimethyl-2-(4,8,12-trimethyltridec-3-en-1-yl)-1,3-dioxane,(E)-6,10,14-trimethyl-2,2-bis(2,2,2-trifluoroethoxy)pentadec-5-ene,(Z)-2,5,5-trimethyl-2-(4,8,12-trimethyltridec-3-en-1-yl)-1,3-dioxane,and (Z)-6,10,14-trimethyl-2,2-bis(2,2,2-trifluoroethoxy)pentadec-5-ene;(R,E)-2,5,5-trimethyl-2-(4,8,12-trimethyltridec-3-en-1-yl)-1,3-dioxane,(R,E)-6,10,14-trimethyl-2,2-bis(2,2,2-trifluoroethoxy)pentadec-5-ene;(R,Z)-2,5,5-trimethyl-2-(4,8,12-trimethyltridec-3-en-1-yl)-1,3-dioxaneand(R,Z)-6,10,14-trimethyl-2,2-bis(2,2,2-trifluoroethoxy)pentadec-5-ene; orselected from the group consisting of2-(4,8-dimethylnonyl)-2,5-dimethyl-1,3-dioxane,6,10-dimethyl-2,2-bis(2,2,2-trifluoroethoxy)undecane,2,5,5-trimethyl-2-(4,8,12-trimethyltridecyl)-1,3-dioxane,6,10,14-trimethyl-2,2-bis(2,2,2-trifluoroethoxy)pentadecane;(R)-2-(4,8-dimethylnonyl)-2,5-dimethyl-1,3-dioxane,(R)-6,10-dimethyl-2,2-bis(2,2,2-trifluoroethoxy)undecane,2,5,5-trimethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)-1,3-dioxane and(6R,10R)-6,10,14-trimethyl-2,2-bis(2,2,2-trifluoroethoxy)pentadecane.

All these ketals are particularly suited for the asymmetrichydrogenation as described above in detail or are the product of saidasymmetric hydrogenation. As mentioned also before the ketals ofunsaturated ketones behave extremely advantageously as compared to thecorresponding ketones.

In the following paragraphs some preferred embodiments of the inventionsare further discussed by means of schematic FIGS. 1 to 6. This, however,is not to be understood as limiting the invention to the embodimentsdescribed here in the figures.

The FIGS. 1 to 3 show the subsequent steps from both6,10-dimethylundec-5-en-2-one and 6,10-dimethylundeca-5,9-dien-2-one to(6R,10R)-6,10,14-trimethylpentadecan-2-one with FIG. 4 showing thesubsequent steps from (6R,10R)-6,10,14-trimethylpentadecan-2-one to(R,R)-isophytol, (2-ambo)-α-tocopherol and (2R,4′R,8′R)-α-tocopherol,respectively.

The reference signs in parentheses in the figures, such as (R-II) areused for identification purposes as described below and are not to beconfused with the indication of formula such as (II) used in the rest ofthis document.

In FIG. 1, three different possibilities for the synthesis of(R)-6,10-dimethylundecan-2-one (R-II) are schematically shown (FIG. 1a), 1 b), 1 c)). As a first step a) for all possibilities shown in FIG.1, a mixture of (E)-6,10-dimethylundec-5-en-2-one and(Z)-6,10-dimethylundec-5-en-2-one or a mixture of(E)-6,10-dimethylundeca-5,9-dien-2-one and(Z)-6,10-dimethylundeca-5,9-dien-2-one (E/Z-I) is provided. In FIG. 1a )the E-isomer (E-I) (i.e. (E)-6,10-dimethylundec-5-en-2-one or(E)-6,10-dimethylundeca-5,9-dien-2-one, respectively) and thecorresponding Z-isomer (Z-I) (i.e (Z)-6,10-dimethylundec-5-en-2-one or(Z)-6,10-dimethylundeca-5,9-dien-2-one, respectively) are separated instep b) from the mixture provided in step a). The separation in step b)is preferably done by distillation over a column. In step c) theZ-isomer is asymmetrically hydrogenated with a specific chiral iridiumcomplex, whereas the E-isomer is asymmetrically hydrogenated with thecorresponding enantiomeric chiral iridium complex. A preferred chiraliridium complex is the one of formula (III). The E-isomer (E-I) isasymmetrically hydrogenated using molecular hydrogen in the presence ofthe chiral iridium complex of formula (IIIa) (S-Ir-complex) having theS-configuration at the stereogenic centre indicated by * in formula(III). The Z-isomer (Z-I), on the other hand, is asymmetricallyhydrogenated using molecular hydrogen in the presence of the chiraliridium complex of formula (IIIb) (R-Ir-complex) having theR-configuration at the stereogenic centre indicated by * in formula(III). Both asymmetric hydrogenation routes furnish the same product,i.e. (R)-6,10-dimethylundecan-2-one (R-II). The double bond at position9 of 6,10-dimethylundeca-5,9-dien-2-one is also hydrogenated during theasymmetric hydrogenation. However, as this double bond is not prochiral,no chiral centre is formed at this position during the hydrogenation.

In FIG. 1b ) only one of the isomers (E-isomer (E-I)) (desired isomer)is asymmetrically hydrogenated as described above for FIG. 1a ). Theother isomer (Z-isomer (Z-I)) (undesired isomer) is subjected tocis/trans isomerization in step α) by addition of a cis/transisomerization catalyst (c/t-cat) and heating. The cis/transisomerization catalyst preferably used is a polythiol, particularly offormula (X). By the action of the cis/trans isomerization catalyst the(Z-isomer (Z-I)) is isomerized to a mixture of the E-isomer and theZ-isomer (E/Z-I) which can be added in step p) to the mixture providedin step a). FIG. 1b ) shows the process in case the E-isomer is thedesired isomer, i.e. the one which is asymmetrically hydrogenated. It isobvious that in case the Z-isomer is the desired isomer, i.e. the onewhich is asymmetrically hydrogenated, the isomerization process wouldapply in an analogous way to that of the E-isomer.

In FIG. 1c ) only one of the isomers (Z-isomer (Z-I)) (desired isomer)is asymmetrically hydrogenated as described above for FIG. 1a ). Acis/trans isomerization catalyst (c/t-cat) is added to the mixture ofthe E-isomer and the Z-isomer (E/Z-I) provided in step a). In step b)the separation of the (desired) isomer (Z-isomer (Z-I)) is done bydistillation in the presence of the cis/trans isomerization catalyst ina (one-pot isomerization or in-situ isomerization). As the desiredisomer is separated by distillation, the remainder, enriched in thehigher boiling isomer, is isomerized so that in the distillation vessela thermodynamic equilibrium between the Z- and E-isomers is formedcontinuously. This procedure may allow all of the undesired isomer beingpresent in the isomer mixture at the beginning provided in step a) to beconverted to the desired isomer. As mentioned, FIG. 1c ) shows theZ-isomer to be the desired isomer (i.e. separated and asymmetricallyhydrogenated), however, it is obvious that the discussion above appliesalso analogously to the case where the E-isomer would be the desiredisomer.

FIG. 2 shows the subsequent step d). In step d)(R)-6,10-dimethylundecan-2-one (R-II) is chemically transformed to amixture of (R,E)-6,10,14-trimethylpentadec-5-en-2-one and(R,Z)-6,10,14-trimethylpentadec-5-en-2-one (E/Z-R-III). FIG. 2 alsoshows the preferred variants of such chemical transformations.

In one of the variants shown in FIG. 2,(7R)-3,7,11-trimethyldodec-1-en-3-ol (R-IIb) is formed from(R)-6,10-dimethylundecan-2-one (R-II) by reacting in a first step, i.e.step d1), (R)-6,10-dimethylundecan-2-one (R-II) with ethyne (acetylene)in the presence of a base (shown is KOH) to yield the intermediate(7R)-3,7,11-trimethyldodec-1-yn-3-ol (R-IIa) and then in second step,i.e. in step d2), reacting with molecular hydrogen in the presence of aLindlar catalyst.

In another variant (7R)-3,7,11-trimethyldodec-1-en-3-ol (R-IIb) isformed directly by means of reaction with a Grignard reagent. In FIG. 2vinylmagnesium chloride is shown as Grignard reagent.

Subsequently, two variants for the conversion of(7R)-3,7,11-trimethyldodec-1-en-3-ol (R-IIb) to the mixture of(R,E)-6,10,14-trimethylpentadec-5-en-2-one and(R,Z)-6,10,14-trimethylpentadec-5-en-2-one (E/Z-R-III) are shown in FIG.2. In the first variant, (7R)-3,7,11-trimethyldodec-1-en-3-ol (R-IIb) isreacted in a Saucy-Marbet reaction (step d3)) with 2-methoxyprop-1-eneto yield a mixture of (R,E)-6,10,14-trimethylpentadec-5-en-2-one and(R,Z)-6,10,14-trimethylpentadec-5-en-2-one (E/Z-R-III). In the secondvariant, (7R)-3,7,11-trimethyldodec-1-en-3-ol (R-IIb) is reacted withalkyl acetoacetate, preferably methyl acetoacetate, in the presence of abase, preferably sodium acetate, to a mixture of(R,E)-6,10,14-trimethylpentadec-5-en-2-one and(R,Z)-6,10,14-trimethylpentadec-5-en-2-one (E/Z-R-III) (Carrollrearrangement).

FIG. 3 shows the subsequent steps e) and f). FIG. 3 corresponds to theFIG. 1 except that the individual substances are extended by a C5 unit.In analogy, at least one isomer of the mixture of(R,E)-6,10,14-trimethylpentadec-5-en-2-one and(R,Z)-6,10,14-trimethylpentadec-5-en-2-one (E/Z-R-III) is separated instep e) and asymmetrically hydrogenated to(6R,10R)-6,10,14-trimethylpentadecan-2-one (R-IV) in step f).

FIG. 4 shows the subsequent steps from(6R,10R)-6,10,14-trimethylpentadecan-2-one to (R,R)-isophytol,(2-ambo)-α-tocopherol, and (2R,4′R,8′R)-α-tocopherol, respectively.

FIG. 4 shows two variants for the conversion of(6R,10R)-6,10,14-trimethylpentadecan-2-one to (R,R)-isophytol. In thefirst variant, (R,R)-isophytol (R-V) is formed from(6R,10R)-6,10,14-trimethylpentadecan-2-one (R-IV) by reacting in a firststep, i.e. step g), (6R,10R)-6,10,14-trimethylpentadecan-2-one (R-IV)with ethyne (acetylene) in the presence of a base (shown is KOH) toyield the intermediate (7R,11R)-3,7,11,15-tetramethylhexadec-1-yn-3-ol(R-IVa) and then in second step, i.e. in step h), reacting withmolecular hydrogen in the presence of a Lindlar catalyst.

In the other variant shown, (R,R)-isophytol (R-V) is formed from(6R,10R)-6,10,14-trimethylpentadecan-2-one (R-IV) by means of reactionwith a Grignard reagent. In FIG. 4 vinylmagnesium chloride is shown asGrignard reagent.

(R,R)-isophytol (R-V) can further be condensed in step m) with2,3,5-trimethylbenzene-1,4-diol to yield (2-ambo)-α-tocopherol(R/S-VI)).

In a further step n) (2R,4′R,8′R)-α-tocopherol (R-VI)) is isolated fromthe corresponding (2-ambo)-α-tocopherol (R/S-VI). The isolation ispreferably done by chromatographic separation by means of a chiralphase.

In FIGS. 5 and 6 preferred embodiments of asymmetric hydrogenations areshown. FIG. 5 refers to the process steps in FIG. 1 and FIG. 6 to theprocess steps of FIG. 3.

The left side of FIG. 5 shows in step c₀) the formation of ketals (E-IK)of (E)-6,10-dimethylundec-5-en-2-one or(E)-6,10-dimethylundeca-5,9-dien-2-one (E-I), respectively (which areobtained after separation of the corresponding isomer mixture in stepb)) using an alcohol (in FIG. 5 ethylene glycol is shown) in thepresence of an acid. The ketal (E-IK), preferably(E)-2-(4,8-dimethylnon-3-en-1-yl)-2-methyl-1,3-dioxolane or(E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2-methyl-1,3-dioxolane,respectively, is then asymmetrically hydrogenated in step c) asdiscussed in FIG. 1. The direct product of this asymmetric hydrogenationis an asymmetrically hydrogenated ketal, i.e. preferably(R)-2-(4,8-dimethylnonyl)-2-methyl-1,3-dioxolane (R-IIK), which afteracidic hydrolysis in step c′) yields (R)-6,10-dimethylundecan-2-one(R-II). On the right side of FIG. 5 the corresponding reaction scheme isshown for the Z-isomer, i.e. (Z)-6,10-dimethylundec-5-en-2-one or(Z)-6,10-dimethylundeca-5,9-dien-2-one (Z-I), respectively, furnishingvia the corresponding ketal intermediate, preferably(Z)-2-(4,8-dimethylnon-3-en-1-yl)-2-methyl-1,3-dioxolane or(Z)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2-methyl-1,3-dioxolane (Z-IK),respectively, the same compound (R)-6,10-dimethylundecan-2-one (R-II).

The left side of FIG. 6 shows in step f_(o)) the formation of ketals(E-R-IIK) of (R,E)-6,10,14-trimethylpentadec-5-en-2-one (E-R-III)obtained after isomer separation in step e) using an alcohol (in FIG. 6ethylene glycol is shown) in the presence of an acid. The ketal(E-R-IIIK), preferably(R,E)-2-methyl-2-(4,8,12-trimethyltridec-3-en-1-yl)-1,3-dioxolane, isthen asymmetrically hydrogenated in step f) as discussed in FIG. 3. Thedirect product of this asymmetric hydrogenation is an asymmetricallyhydrogenated ketal, i.e.2-methyl-2-((4R,8R)-4,8,12-trimethyltridecyl)-1,3-dioxolane (R-IVK),which after acidic hydrolysis in step f′) yields(6R,10R)-6,10,14-trimethylpentadecan-2-one (R-IV). On the right side ofFIG. 6 the corresponding reaction scheme is shown for the Z-isomer, i.e.(R,Z)-6,10,14-trimethylpentadec-5-en-2-one (Z-R-III), furnishing via theketal intermediate, preferably(Z,E)-2-methyl-2-(4,8,12-trimethyltridec-3-en-1-yl)-1,3-dioxolane(Z-R-IIIK), the same compound(6R,10R)-6,10,14-triniethylpentadecan-2-one (R-IV).

EXAMPLES

The present invention is further illustrated by the followingexperiments.

Analytical Methods

GC Determination of E/Z-Ratio and/or Purity of6,10-dimethylundec-5-en-2-one (DHGA), (R)-6,10-dimethylundecan-2-one(THGA) and (R)-6,10,14-trimethylpentadec-5-en-2-one (R-THFA):

Agilent 6850, column DB-5HT (30 m, 0.25 mm diameter, 0.10 μm filmthickness), 107 kPa helium carrier gas). The samples were injected assolutions in hexane, split ratio 300:1, injector temperature 200° C.,detector temperature 350° C. Oven temperature program: 100° C. (8 min),10° C./min to 200° C. (1 min), 20° C./min to 220° C. (4 min), runtime 24min.GC Determination of Purity of (6R,10R)-6,10,14-trimethylpentadecan-2-oneAgilent 6850, column DB-5HT (30 m, 0.25 mm diameter, 0.10 μm filmthickness), 115 kPa helium carrier gas). The samples were injected assolutions in hexane, split ratio 300:1, injector temperature 200° C.,detector temperature 350° C. Oven temperature program: 120° C. (5 min),14° C./min to 260° C. (2 min), 20° C./min to 280° C. (4 min), runtime 22min.GC Determination of Purity of(3RS,7R,11R)-3,7,11,15-tetramethylhexadec-1-en-3-ol ((R,R)-Isophytol)Agilent 6850 instrument equipped with FID. Agilent DB-5 column (30 m,0.32 mm diameter, 0.25 μm film thickness) with 25 psi molecular hydrogencarrier gas. The samples were injected as solutions in acetonitrile witha split ratio of 50:1. Injector temperature: 250° C., detectortemperature: 350° C. Oven temperature program: 100° C., 4° C./min to250° C.GC Determination of E/Z-Ratio and/or Purity of6,10-dimethylundeca-5,9-dien-2-one and Ketals:Agilent 6850 instrument, column Agilent DB-5 (123-5032E, 30 m×0.32 mm,film 0.25 μm), the samples were injected as solutions in acetonitrile,split ratio 50:1, injector 250° C., detector 350° C. Oven temperatureprogram: 100° C., 4° C./min until 250° C., 37.5 min total runtime.

Retention times (t_(R)): min. (E)-6,10-dimethylundeca-5,9-dien-2-one(E-GA) 11.0 E-GA-DM 14.8 E-GA-neo 20.5 E-GA-tfe 13.2, pc¹(Z)-6,10-dimethylundeca-5,9-dien-2-one (Z-GA) 10.6 Z-GA-DM 14.0, pc¹Z-GA-neo 19.5 E-DHGA-DM 14.1, pc¹ E-DHGA-neo 19.6, pc¹ E-DHGA-tfe 12.5Z-DHGA-DM 13.0, pc¹ Z-DHGA-neo 18.5, pc¹ R,E-THFA-DM 24.2, pc¹R,E-THFA-neo 29.1 R,Z-THFA-DM 23.1, pc¹ R,Z-THFA-neo 27.9 R-THGA-DM 13.1R-THGA-neo 18.9 R-THGA-tfe 11.8 RR-C18-DM decomp.² RR-C18-neo 28.5RR-C18-tfe 21.4 ¹pc = partial decomposition ²decomp. = decompositionduring GC analysisAnalysis of the Asymmetrically Hydrogenated Reaction Products

The corresponding dimethyl, ethylene glycol, neopentyl andbis(trifluoroethyl) ketals were hydrolyzed to the ketones in thepresence of aqueous acid and analyzed for conversion and theirstereoisomer ratio using the following methods for ketones.

The conversion of the hydrogenation reaction was determined by gaschromatography using an achiral column.

Method for Conversion:

Agilent 7890A GC equipped with FID. Agilent HP-5 column (30 m, 0.32 mmdiameter, 0.25 μm film thickness) with 25 psi molecular hydrogen carriergas. The samples were injected as solutions in dichloromethane with asplit ratio of 10:1. Injector temperature: 250° C., detectortemperature: 300° C. Oven temperature program: 50° C. (2 min) then 15°C./min to 300° C., hold 5 min.

For the determination of the isomer ratio, the hydrogenated ketones canbe reacted with either(+)-diisopropyl-O,O′-bis(trimethylsilyl)-L-tartrate or(−)-diisopropyl-O,O′-bis(trimethylsilyl)-D-tartrate in the presence oftrimethylsilyl triflate [Si(CH₃)₃(OSO₂CF₃)] to form the diastereomericketals as described in A. Knierzinger, W. Walther, B. Weber, R. K.Müller, T. Netscher, Helv. Chin. Acta 1990, 73, 1087-1107. The ketalscan be analysed by gas chromatography using an achiral column todetermine the isomer ratios. For the hydrogenated ketone6,10-dimethylundecan-2-one, either D-(−)- or L-(+)-diisopropyltartratecan be used. For 6,10,14-trimethylpentadecan-2-one,L-(+)-diisopropyltartrate can be used to measure the quantity of the(6R,10R)-isomer that was present. D-(−)-diisopropyltartrate can be usedto determine the amount of the (6S,10S)-isomer. Thus the selectivity ofthe stereoselective hydrogenation can be determined indirectly.

Method for Determination of Isomers:

Agilent 6890N GC with FID. Agilent CP-Sil88 for FAME column (60 m, 0.25mm diameter, 0.20 μm film thickness) with 16 psi molecular hydrogencarrier gas. The samples were injected as solutions in ethyl acetatewith a split ratio of 5:1. Injector temperature: 250° C., FID detectortemperature: 250° C. Oven temperature program: 165° C. (isothermal, 240min)

The Ir complexes indicated in the following experiments are preparedaccording to the disclosure in Chem. Sci., 2010, 1, 72-78.

Experiment E1 Separation of E/Z Isomer Mixtures of6,10-dimethylundec-5-en-2-one (Step b)

7.02 kg of 6,10-dimethylundec-5-en-2-one was prepared according toexample 10 of DE 1 193 490 and was analysed by the GC method given aboveto be a 57%/43% mixture of (E)-6,10-dimethylundec-5-en-2-one and(Z)-6,10-dimethylundec-5-en-2-one (99% purity).

The mixture was distilled using separation equipment consisting of astill (volume: 9 liter) with a falling film evaporator, a rectifyingcolumn (70 mm inner diameter, height 5 m). The column was equipped witha very efficient structured packing (Sulzer). The mixture was rectifiedat a top pressure of approx. 5 mbar and at a column top temperature inthe range from 105 to 112° C. and a bottom temperature in the still ofabout 125° C. The reflux ratio was adjusted to 20.

Fractions containing (Z)-6,10-dimethylundec-5-en-2-one (content ofZ-isomer=99%, E-isomer<1%) as well as fractions containing(E)-6,10-dimethylundec-5-en-2-one (content of E-isomer 97%, Z-isomer<3%)were collected. At the end (E)-6,10-dimethylundec-5-en-2-one (content ofE-isomer=99.5%, Z-isomer=0.5%) was found left in the still.

Experiment E2 Asymmetric Hydrogenations of 6,10-dimethylundec-5-en-2-oneor 6,10-dimethylundeca-5,9-dien-2-one (Step c)

Both isomers (E)-6,10-dimethylundec-5-en-2-one (E-DHGA) (E/Z=99.5/0.5)and (Z)-6,10-dimethylundec-5-en-2-one (Z-DHGA) (Z/E=99/1) werehydrogenated asymmetrically, separate from each other in the followingmanner:

A 2 L autoclave was charged with 70 g (0.353 mol) of the specificisomer, 700 mL of 2,2,2-trifluoroethanol and a solution of the chiraliridium complex of formula (III-F) having the chirality given in table 2at the centre indicated by * in said formula (570 mg, 0.356 mmol, 0.1mol %) in anhydrous dichloromethane (10 g). The autoclave was closed anda pressure of 50 bar of molecular hydrogen was applied. The reactionmixture was heated to 30° C. whilst stirring for 2 hours. Afterwards thepressure was released and the solvent was removed. The product formed is(R)-6,10-dimethylundecan-2-one. The conversion as well as the amount ofisomers formed is determined as indicated above and the results aregiven in table 2. The products of the two separate asymmetrichydrogenations have been combined.

TABLE 2 Asymmetric hydrogenation of E-DHGA and Z-DHGA. E-DHGA Z-DHGAFormula of Ir complex III-F III-F Configuration of chiral Ir complexat * S R Amount of chiral Ir complex [mol-%] 0.1 0.1 Conversion[%] >99 >99 (R)-6,10-dimethylundecan-2-one [%] 95.8 93.3(S)-6,10-dimethylundecan-2-one [%] 4.2 6.7

In a further experiment 0.25 mmol of(E)-6,10-dimethylundeca-5,9-dien-2-one (E-GA) or(E)-6,10-dimethylundec-5-en-2-one (E-DHGA) and 0.5 mol-%, respectively 1mol-%, of the Ir complex of the formula given in table 2a and 1.25 ml ofabsolute (dry) dichloromethane were put in an autoclave. The autoclavewas closed and a pressure of 50 bar of molecular hydrogen was applied.Under stirring the reaction solution was kept at room temperature for 14hours. Afterwards the pressure was released and the solvent removed. Fordetermining the conversion the crude product was analysed by achiral gaschromatography without any further purification. The amount for theisomers has been determined using the above method.

TABLE 2a Asymmetric hydrogenation of E-GA or E-DHGA. 1 2 3 4 E-GA E-GAE-DHGA E-DHGA Formula of Ir complex III-F III-C III-D III-CConfiguration of chiral S S S S Ir complex at * Amount of chiral Ir 0.50.5 1 1 complex [mol-%] Conversion [%] 100 100 100 100Isomer-Distribution (6R)-6,10-dimethyl- 96.5 >98 98.6 98.9 undecan-2-one[%] (6S)-6,10-dimethyl- 3.5 <2 1.4 1.1 undecan-2-one [%]

In two further experiments in an autoclave 0.25 mmol of(E)-6,10-dimethylundec-5-en-2-one (E-DHGA) or(Z)-6,10-dimethylundec-5-en-2-one (Z-DHGA) and 1 mol-% of the Ir complexof the formula given in table 2b or 2c or 2d and 1.25 ml of absolute(dry) solvent as indicated in table 2b or 2c were put. The autoclave wasclosed and a pressure of 50 bar of molecular hydrogen was applied. Understirring the reaction solution was kept at room temperature for 16hours. Afterwards the pressure was released and the solvent removed. Fordetermining the conversion the crude product was analyzed by achiral gaschromatography without any further purification. The amount for theisomers has been determined using the above method.

TABLE 2b Asymmetric hydrogenation of E-DHGA with different Ir complexes.5 6 7 8 E-DHGA E-DHGA E-DHGA E-DHGA Formula of Ir complex III-D III-CIII-D III-A′² Configuration of chiral Ir R S R S complex at * Amount ofchiral Ir complex 1 1 1 1 [mol-%] Solvent¹ TFE DCM DCM DCM Conversion[%] >99 >99 >99 >99 Isomer-Distribution (6R)-6,10-dimethylundecan- 0.798.9 1.4 89.1 2-one [%] (6S)-6,10-dimethylundecan- 99.3 1.1 98.6 10.92-one [%] ¹TFE = 2,2,2-trifluoroethanol; DCM = dichloromethane ²chiralIr complex of formula (III-A′):

TABLE 2c Asymmetric hydrogenation of E-DHGA with different Ir complexes.9 10 11 E-DHGA E-DHGA E-DH GA X¹═X² in formula of Ir complex¹

Configuration of chiral (S) (S) (S) Ir complex at * Amount of chiral Ir1 1 1 complex [mol-%] Solvent¹ DCM DCM DCM Conversion [%] >99 >99 >99Isomer-Distribution (6R)-6,10-dimethyl- 94.5 94.2 90.6 undecan-2-one [%](6S)-6,10-dimethyl- 5.5 5.8 9.4 undecan-2-one [%] ¹chiral Ir complex offormula

²TFE = 2,2,2-trifluoroethanol; DCM = dichloromethane

TABLE 2d Asymmetric hydrogenation of Z-DHGA with different Ir complexes.12 13 14 15 Z-DHGA Z-DHGA Z-DHGA Z-DHGA Formula of Ir complex III-DIII-D III-C III-A′² Configuration of chiral Ir R S S S complex at *Amount of chiral Ir complex 1 1 1 1 [mol-%] Solvent¹ TFE DCM DCM DCMConversion [%] >99 >99 >99 >99 Isomer-Distribution(6R)-6,10-dimethylundecan- 99.3 1.7 2.1 11.1 2-one [%](6S)-6,10-dimethylundecan- 0.7 98.3 97.9 88.9 2-one [%] ¹TFE =2,2,2-trifluoroethanol; DCM = dichloromethane ²chiral Ir complex offormula (III-A′):

Experiment E2a Preparation of Ketals of 6,10-dimethylundec-5-en-2-one or6,10-dimethylundeca-5,9-dien-2-one (Step c_(o))

a) Preparation of Dimethyl Ketals

6,10-dimethylundec-5-en-2-one or 6,10-dimethylundeca-5,9-dien-2-one(170.5 mmol) was added to trimethyl orthoformate (50.8 mL, 49.2 g, 451mmol, 2.65 eq.) and cooled to 5° C. Sulfuric acid (96%, 32.3 mg, 0.29mmol, 0.2 mol %) in MeOH (16 mL) was added within 5 min. Subsequently,the reaction was heated to reflux (65° C. IT) for 3 h. After cooling,thin layer chromatography (TLC) analysis indicated full conversion.NaOMe (0.24 mL of a 25% solution in MeOH) was added to neutralize theacid. The mixture was concentrated in vacuo and subsequently dilutedwith hexane (50 mL). The developed precipitate was filtered off and thefiltrate was concentrated. The crude product was purified bydistillation, furnishing the desired dimethyl ketal.

The characterization of the ketal is given in detail hereafter.

TABLE 2 d(i) Preparation of dimethyl ketals. E-GA-DM Z-GA-DM E-DHGA-DMZ-DHGA-DM Ketone (E)-6,10- (Z)-6,10- (E)-6,10- (Z)-6,10- dimethyl-dimethyl- dimethyl- dimethyl- undeca- undeca- undec-5-en- undec-5-en-5,9-dien- 5,9-dien- 2-one 2-one 2-one 2-one Ketal (E)-10,10- (Z)-10,10-(E)-2,2- (Z)-2,2- dimethoxy- dimethoxy- dimethoxy- dimethoxy-2,6-dimeth- 2,6-dimeth- 6,10-dimeth- 6,10-dimeth- ylundeca- ylundeca-ylundec- ylundec- 2,6-diene 2,6-diene 5-ene 5-ene Yield 87 73 91 98 [%]E/Z 99.4/0.6 1.6/98.4 95.4/4.6 0.4/99.6

Characterization Data (E)-10,10-dimethoxy-2,6-dimethylundeca-2,6-diene(E-GA-DM)

¹H NMR (300 MHz, CDCl₃): δ 1.26 (s, 3H), 1.58 (s, 3H), 1.60 (s, 3H),superimposed by 1.60-1.65 (m, 2H), 1.66 (br s, 3H), 1.92-2.09 (m, 6H),3.17 (s, 6H), 5.02-5.14 (m, 2H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ 15.9 (1C), 17.6 (1C), 20.8 (1C), 22.8 (1C),25.6 (1C), 26.6 (1C) 36.4 (1C), 39.6 (1C), 47.9 (2C), 101.4 (1C), 123.8(1C), 124.2 (1C), 131.2 (1C), 135.1 (1C) ppm.

MS (EI, m/z): 240 (M⁺, <1), 225.3 [(M-CH₃)⁺, 1], 209.3 [(M-CH₃O)⁺, 20],193.3 (8), 176.2 (18), 161.2 (16), 139.2 (20), 123.2 (14), 107.2 (75),89.2 (100), 69.2 (65), 41.1 (56).

IR (cm⁻¹): 2928 (m), 2857 (w), 2828 (w), 1670 (w), 1452 (m), 1376 (s),1345 (w), 1302 (w), 1262 (w), 1222 (w), 1196 (m), 1172 (m), 1123 (s),1102 (s), 1053 (s), 985 (w), 929 (w), 854 (s), 744 (w), 619 (w).

(Z)-10,10-dimethoxy-2,6-dimethylundeca-2,6-diene (Z-GA-DM)

¹H NMR (300 MHz, CDCl3): δ 1.27 (s, 3H), 1.56-1.65 (m, 5H), 1.68 (br. s,6H), 1.96-2.09 (m, 6H), 3.17 (s, 6H), 5.11 (t, J=7.2 Hz, 2H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ 17.6 (1C), 20.9 (1C), 22.7 (1C), 23.3 (1C),25.7 (1C), 26.6 (1C), 31.9 (1C), 36.7 (1C), 48.0 (2C), 101.4 (1C), 124.2(1C) 124.6 (1C), 131.5 (1C), 135.4 (1C) ppm.

MS (EI, m/z): No GC-MS was obtained due to decomposition on the column.

IR (cm⁻¹): 2943 (m), 2858 (w), 2828 (w), 1451 (m), 1376 (m), 1348 (w),1301 (w), 1261 (w), 1197 (m), 1172 (m), 1153 (w), 1120 (s), 1098 (m),1053 (s), 929 (w), 854 (m), 833 (m), 745 (w), 622 (w).

(E)-2,2-dimethoxy-6,10-dimethylundec-5-ene (E-DHGA-DM)

¹H NMR (300 MHz, CDCl₃): δ 0.83 (d, J=6.6 Hz, 6H), 1.02-1.13 (m, 2H),1.24 (s, 3H), 1.27-1.39 (m, 2H), 1.49 (tqq, J=6.4, 6.4, 6.4 Hz, 1H),superimposed by 1.53-1.63 (m, 2H), superimposed by 1.56 (s, 3H),1.87-2.03 (m, 4H), 3.13 (s, 6H), 5.07 (tq, J=7.0, 1.4 Hz, 1H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ 16.1 (1C), 21.2 (1C), 23.0 (2C), 23.2 (1C),26.0 (1C), 28.2 (1C), 36.9 (1C), 39.0 (1C), 40.2 (1C), 48.3 (2C), 101.8(1C), 124.0 (1C), 135.9 (1C) ppm.

MS (EI, m/z): No GC-MS was obtained due to decomposition on the column.

IR (cm⁻¹): 2953 (s), 2931 (s), 2870 (m), 2828 (m), 2108 (w), 1668 (w),1460 (m), 1377 (s), 1367 (m), 1345 (w), 1301 (w), 1262 (m), 1221 (m),1198 (m), 1172 (s), 1119 (s), 1100 (s), 1077 (s), 1053 (s), 967 (w), 927(w), 854 (w), 796 (w), 739 (w), 620 (w).

6Z)-2,2-di meth oxy-6,10-di methylundec-5-ene (Z-DHGA-DM)

¹H NMR (300 MHz, CDCl₃): δ 0.88 (d, J=6.6 Hz, 6H), 1.12-1.21 (m, 2H),1.28 (s, 3H), 1.32-1.43 (m, 2H), 1.53 (dspt, J=6.6, 6.6 Hz, 1H),1.57-1.66 (m, 2H), 1.68 (q, J=1.1 Hz, 3H), 1.94-2.06 (m, 4H), 3.18 (s,6H), 5.10 (t, J=6.8 Hz, 1H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ 20.9 (1C), 22.6 (2C), 22.7 (1C), 23.3 (1C),25.8 (1C), 27.9 (1C), 31.9 (1C), 36.8 (1C), 38.9 (1C), 48.0 (2C), 101.5(1C), 124.3 (1C), 135.9 (1C) ppm.

MS (EI, m/z): No GC-MS was obtained due to decomposition on the column.

IR (cm⁻¹): 2953 (s), 2870 (w), 2828 (w), 1461 (w), 1376 (m), 1301 (w),1261 (w), 1205 (m), 1172 (m), 1119 (m), 1097 (m), 1074 (m), 1053 (s),1022 (w), 927 (w), 854 (m), 738 (w), 621 (w).

b) Preparation of Ethylene Glycol Ketals

Under nitrogen, a reaction vessel was charged with glycol (112 mL, 125g, 2.1 mol), p-toluenesulfonic acid monohydrate (0.150 g, 0.5774 mmol)and 0.5 mol either of (E)-6,10-dimethylundec-5-en-2-one or(Z)-6,10-dimethylundec-5-en-2-one. The mixture was allowed to stir atambient temperature for 5 hours at reduced pressure (0.39 mbar). Whilemaintaining the low pressure, the temperature was slowly increased to40° C. At conversion of larger than 95% of the ketone, the temperaturewas further increased allowing a gentle distillation of glycol andcontinued until a conversion of more than 99% was achieved.

At room temperature, the product was extracted by a solution oftriethylamine in heptane (2 mL triethylamine/L heptane). The glycolphase was separated and the heptane layer was washed with a NaHCO₃solution in water. Separation of the heptane phase, drying overanhydrous Na₂SO₄, filtration and removal of the solvent in vacuo gavethe crude ketal. The ketal was further purified by means ofdistillation. The corresponding ketal was identified by ¹H-NMR.

TABLE 2 d(ii) Preparation of ethylene glycol ketals. E-DHGA-en Z-DHGA-enKetone (E)-6,10-dimethylundec- (Z)-6,10-dimethylundec- 5-en-2-one5-en-2-one Ketal (E)-2-(4,8-dimethylnon-3- (Z)-2-(4,8-dimethylnon-3-en-1-yl)-2-methyl-1,3- en-1-yl)-2-methyl-1,3- dioxolane dioxolane Yield[%] 88 87

Characterization Data(E)-2-(4,8-dimethylnon-3-en-1-yl)-2-methyl-1,3-dioxolane (E-DHGA-en)

¹H NMR (300 MHz, CDCl₃) δ 5.12 (t, 1H), 3.95 (m, 4H), 2.2-2 (m, 2H),1.94 (t, 2H), 1.8-1.3 (m, 11H), 1.2-1.0 (m, 2H), 0.87 (d, 6H) ppm.

(Z)-2-(4,8-dimethylnon-3-en-1-yl)-2-methyl-1,3-dioxolane (Z-DHGA-en)

¹H NMR (300 MHz, CDCl₃) δ 5.12 (t, 1H), 3.94 (m, 4H), 2.15-1.9 (m, 4H),1.7-1.45 (m, 6H), 1.44-1.27 (m, 5H), 1.23-1.08 (m, 2H), 0.88 (d, 6H)ppm.

c) Preparation of Neopentyl Glycol Ketals

The ketone (90.7 mmol) indicated in table 2 d(iii),2,2-dimethyl-1,3-propanediol (neopentylglycol, 32.4 g, 283 mmol, 3.4eq.) and p-toluene sulfonic acid monohydrate (60 mg, 0.31 mmol, 0.3 mol%) were suspended in toluene (300 mL). The reaction was heated to 90° C.upon which a homogeneous solution formed. Subsequently, at 75° C.,vacuum was applied cautiously (first 63 mbar, then 24 mbar) in order toslowly distill toluene off (approx. 100 mL over 4 h). After 4 h, thinlayer chromatography (TLC) analysis indicated full conversion of theketone. The reaction was allowed to cool to room temperature and dilutedwith heptane (300 mL) upon which excess neopentylglycol precipitated.The precipitate was filtered off (17.4 g wet). The filtrate was treatedwith Et₃N (1 mL), subsequently washed with aqueous NaHCO₃ solution (2.4%w/w, 2×300 mL), dried over MgSO₄ and concentrated in vacuo. The crudeproduct was purified by distillation, furnishing the desired neopentylketal. The characterization of the ketal is given in detail hereafter.

TABLE 2 d(iii) Preparation of neopentyl glycol ketals. E-GA-neo Z-GA-neoE-DHGA-neo Z-DHGA-neo Ketone (E)-6,10- (Z)-6,10- (E)-6,10- (Z)-6,10-dimethyl- dimethyl- dimethyl- dimethyl- undeca-5,9- undeca-5,9-undec-5-en- undec-5-en- dien-2-one dien-2-one 2-one 2-one Ketal(E)-2-(4,8- (Z)-2-(4,8- (E)-2-(4,8- (Z)-2-(4,8- dimethyl- dimethyl-dimethyl- dimethyl- nona-3,7- nona-3,7- non-3-en- non-3-en- dien-1-yl)-dien-1-yl)- 1-yl)-2,5,5- 1-yl)-2,5,5- 2,5,5- 2,5,5- trimethyl-trimethyl- trimethyl- trimethyl- 1,3-dioxane 1,3-dioxane 1,3-dioxane1,3-dioxane Yield 78 87 89 84 [%] E/Z 99.4/0.6 1.7/98.3 95.3/4.71.6/98.4

Characterization Data(E)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2,5,5-trimethyl-1,3-dioxane(E-GA-neo)

¹H NMR (300 MHz, CDCl₃): δ 0.92 (s, 3H), 0.99 (s, 3H), 1.37 (s, 3H),1.59 (s, 3H), 1.61 (s, 3H), 1.67 (s, 3H), 1.68-1.75 (m, 2H), 1.94-2.15(m, 6H), AB signal (δ_(A)=3.46, δ_(B)=3.52, J_(AB)=11.3 Hz, 4H),5.05-5.17 (m, 2H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ 15.9 (1C), 17.6 (1C), 20.8 (1C), 22.0 (1C),22.6 (1C), 22.7 (1C), 25.6 (1C), 26.7 (1C), 29.9 (1C), 37.3 (1C), 39.6(1C), 70.3 (2C), 98.8 (1C), 124.1 (1C), 124.3 (1C), 131.2 (1C), 135.1(1C) ppm.

MS (EI, m/z): 280 (M⁺, 3), 265 [(M-CH₃)⁺, 14], 176 (21), 129[(C₇H₁₃O₂)⁺, 100], 69 (63), 43 (43).

IR (cm⁻¹): 2954 (m), 2925 (m), 2858 (m), 2731 (w), 1720 (w), 1669 (w),1473 (w), 1450 (m), 1394 (m), 1372 (m), 1349 (w), 1306 (w), 1271 (w),1249 (m), 1211 (m), 1186 (m), 1123 (s), 1088 (s), 1043 (m), 1021 (m),984 (w), 950 (w), 925 (w), 907 (w), 862 (m), 837 (w), 792 (w), 742 (w),677 (w), 667 (w).

(Z)-2-(4,8-dimethylnona-3,7-dien-1-yl)-2,5,5-trimethyl-1,3-dioxane(Z-GA-neo)

¹H NMR (300 MHz, CDCl₃): δ 0.91 (s, 3H), 0.97 (s, 3H), 1.35 (s, 3H),1.60 (s, 3H), 1.64-1.74 (m, 5H) superimposed by 1.67 (br s, 3H),1.99-2.18 (m, 6H), AB signal (δ_(A)=3.44, δ_(B)=3.51, J_(AB)=11.3 Hz,4H), 5.07-5.16 (m, 2H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ 17.5 (1C), 20.9 (1C), 21.3 (1C), 21.9 (1C),22.5 (1C), 22.6 (1C), 23.3 (1C), 25.7 (1C), 26.6 (1C), 29.9 (1C), 31.8(1C), 37.5 (1C), 70.3 (1C), 98.7 (1C), 124.3 (1C), 124.9 (1C), 131.4(1C), 135.2 (1C) ppm.

MS (EI, m/z): 280 (M⁺, 3), 265 [(M-CH₃)⁺, 13], 176 (19), 129[(C₇H₁₃O₂)⁺, 100], 107 (15), 69 (62), 43 (39).

IR (cm⁻¹): 2954 (m), 2927 (m), 2858 (m), 2729 (w), 1721 (w), 1671 (w),1473 (m), 1450 (m), 1394 (m), 1374 (m), 1349 (w), 1315 (w), 1271 (m),1249 (m), 1211 (m), 1187 (m), 1149 (w), 1120 (s), 1086 (s), 1043 (m),1021 (m), 985 (w), 951 (m), 925 (w), 907 (m), 857 (m), 833 (m), 792 (w),743 (w), 677 (w), 667 (w).

(E)-2-(4,8-dimethylnon-3-en-1-yl)-2,5,5-trimethyl-1,3-dioxane(E-DHGA-neo)

¹H NMR (300 MHz, CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 0.93 (s, 3H), 1.00(s, 3H), 1.06-1.22 (m, 2H), 1.31-1.43 (m, 2H) superimposed by 1.38 (s,3H), 1.53 (tqq, J=6.6, 6.6, 6.6 Hz, 1H), 1.61 (br s, 3H), 1.65-1.77 (m,2H), 1.94 (t, J=7.5 Hz, 2H), 2.05-2.17 (m, 2H), AB signal (δ_(A)=3.46,δ_(B)=3.54, J_(AB)=11.4 Hz, 4H), 5.13 (tq, J=7.1, 1.1 Hz, 1H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ 15.8 (1C), 20.9 (1C), 22.0 (1C), 22.59 (1C),22.63 (2C), 22.7 (1C), 25.7 (1C), 27.9 (1C), 29.9 (1C), 37.3 (1C), 38.6(1C), 39.9 (1C), 70.3 (2C), 98.8 (1C), 123.8 (1C), 135.6 (1C) ppm.

MS (EI, m/z): 282 (M⁺, 5), 267 [(M-CH₃)⁺, 10), 129 (100), 95 (14), 69(36), 43 (32).

IR (cm⁻¹): 2953 (s), 2929 (m), 2868 (m), 1720 (w), 1468 (m), 1394 (m),1381 (m), 1368 (m), 1349 (w), 1306 (w), 1270 (w), 1250 (m), 1211 (m),1187 (w), 1118 (s), 1087 (s), 1066 (m), 1044 (m), 1022 (m), 950 (m), 925(w), 907 (m), 862 (m), 791 (w), 739 (w), 677 (w), 666 (w).

(Z)-2-(4,8-dimethylnon-3-en-1-yl)-2,5,5-trimethyl-1,3-dioxane(Z-DHGA-neo)

¹H NMR (300 MHz, CDCl₃): δ 0.87 (d, J=6.6 Hz, 6H), 0.93 (s, 3H), 0.97(s, 3H), 1.10-1.20 (m, 2H), 1.34-1.41 (m, 3H) superimposed by 1.36 (s,3H), 1.53 (tqq, J=6.6, 6.6, 6.6 Hz, 1H), 1.64-1.75 (m, 2H) superimposedby 1.67 (q, J=1.5 Hz, 3H), 1.95-2.15 (m, 4H), AB signal (δ_(A)=3.46,δ_(B)=3.51, J_(AB)=11.1 Hz, 4H), 5.12 (br t, J=7.2 Hz, 1H)

¹³C NMR (75 MHz, CDCl₃): δ 21.1 (1C), 22.0 (1C), 22.61 (3C), 22.65 (1C),23.4 (1C), 25.7 (1C), 27.9 (1C), 29.9 (1C), 31.9 (1C), 37.2 (1C), 38.8(1C), 70.3 (2C), 98.8 (1C), 124.6 (1C), 135.8 (1C) ppm.

MS (EI, m/z): 282 (M⁺, 6), 267 [(M-CH₃)⁺, 11), 129 (100), 95 (14), 69(35), 43 (32).

IR (cm⁻¹): 2953 (s), 2867 (m), 1722 (w), 1468 (m), 1394 (m), 1368 (m),1349 (w), 1306 (w), 1270 (w), 1250 (m), 1211 (m), 1189 (w), 1116 (s),1086 (s), 1043 (m), 1022 (m), 951 (m), 925 (w), 907 (m), 856 (m), 792(w), 739 (w), 677 (w), 667 (w).

d) Preparation of bis(trifluoroethyl) Ketals

A 250 mL three-necked flask with stir bar was dried under high vacuum(heat gun at 250° C.), then allowed to cool, flushed with argon andcharged with 1,1,1 trifluoroethanol (TFE) (40 mL) under argon. The flaskwas cooled with an ice-bath while trimethylaluminum (2 M in heptane,20.0 mL, 40.0 mmol, 1.95 eq.) was added dropwise within 60 min, keepingthe temperature below 22° C. The two-phase (TFE/heptane) mixture becameclear again after a few minutes and was allowed to stir for anadditional 20 min at room temperature. 20.7 mmol of(E)-10,10-dimethoxy-2,6-dimethylundeca-2,6-diene (E-GA-DM) or(E)-2,2-dimethoxy-6,10-dimethylundec-5-ene (E-DHGA-DM), prepared asshown above, was added dropwise within 5 min at room temperature. After1.5 h, GC analysis indicated full conversion of starting material. Thereaction was quenched with a half-saturated solution of potassium sodiumtartrate in water (100 mL), stirred for 2 h at room temperature andfinally diluted with n-hexane (200 mL). The organic phase was separated,extracted with n-hexane (2×100 mL), dried over MgSO₄ and concentrated.The crude product was purified by column chromatography (neutralaluminium oxide, eluent: n-hexane). The characterization of the ketal isgiven in detail hereafter.

TABLE 2 d(iv) Preparation of bis(trifluoroethyl) ketals. E-GA-tfeE-DHGA-tfe Dimethylketal E-GA-DM E-DHGA-DM (reactant) Ketal(E)-2,6-dimethyl-10,10- (E)-6,10-dimethyl-2,2- bis(2,2,2-trifluoro-bis(2,2,2-trifluoro- ethoxy)undeca-2,6-diene ethoxy)undec-5-ene Yield[%] 85 74 E/Z 99.4/0.6 95.0:5.0

Characterization Data(E)-2,6-dimethyl-10,10-bis(2,2,2-trifluoroethoxy)undeca-2,6-diene(E-GA-tfe)

¹H NMR (300 MHz, CDCl₃): δ 1.41 (s, 3H), 1.62 (br s, 6H), 1.67-1.76 (m,2H), superimposed by 1.69 (q, J=0.9 Hz, 3H), 1.93-2.15 (m, 6H),3.73-3.97 (m, 4H), 5.02-5.18 (m, 2H) ppm.

¹³C NMR (150 MHz, CDCl₃): δ 15.9 (1C), 17.6 (1C), 21.3 (1C), 22.6 (1C),25.7 (1C), 26.6 (1C), 36.9 (1C), 39.6 (1C), 59.3 (q, J_(C,F)=35.0 Hz,2C), 103.4 (1C), 124.0 (q, J_(C,F)=275.0 Hz, 2C), 122.7 (1C), 124.1(1C), 131.5 (1C), 136.2 (1C) ppm.

MS (EI, m/z): 361 [(M-CH₃)⁺, 1], 276 [(M-TFE)⁺, 15], 225[(CF₃CH₂O)₂C—CH₃)⁺, 86], 207 (20), 153 (18), 136 (58), 107 (80), 69(100), 41 (40).

IR (cm⁻¹): 2927 (w), 2859 (w), 1459 (w), 1419 (w), 1385 (w), 1281 (s),1223 (w), 1156 (s), 1133 (s), 1081 (s), 971 (s), 889 (m), 860 (w), 845(w), 678 (w), 663 (w).

(E)-6,10-dimethyl-2,2-bis(2,2,2-trifluoroethoxy)undec-5-ene (E-DHGA-tfe)

¹H NMR (600 MHz, CDCl₃): δ 0.88 (d, J=6.8 Hz, 6H), 1.11-1.17 (m, 2H),1.35-1.40 (m, 2H), 1.41 (s, 3H), 1.54 (qqt, J=6.7, 6.7, 6.7 Hz, 1H),1.61 (br s, 3H), 1.69-1.73 (m, 2H), 1.95 (t, J=7.7 Hz, 2H), 2.03-2.09(m, 2H), 3.78-3.91 (m, 4H), 5.09 (tq, J=7.1, 1.3 Hz, 1H) ppm.

¹³C NMR (151 MHz, CDCl₃): δ 14.1 (1C), 15.8 (1C), 21.3 (1C), 22.56 (1C),22.61 (1C), 25.6 (1C), 27.9 (1C), 37.0 (1C), 38.6 (1C), 39.8 (1C), 59.2(q, J_(C,F)=35.0 Hz, 2C), 103.4 (1C), 124.0 (q, J_(C,F)=277.0 Hz, 2C),122.4 (1C), 136.7 (1C) ppm.

MS (EI, m/z): 363 [(M-CH₃)⁺, 1], 278 [(M-TFE)⁺, 22], 225[(CF₃CH₂O)₂C—CH₃)⁺, 60], 193 (100), 153 (13), 127 (11), 83 (CF₃CH₂ ⁺,25), 69 (13), 43 (17).

IR (cm⁻¹): 2956 (w), 2933 (w), 2872 (w), 1462 (w), 1419 (w), 1385 (w),1368 (w), 1281 (s), 1223 (w), 1156 (s), 1134 (s), 1081 (s), 971 (s), 889(m), 860 (w), 845 (w), 679 (w), 663 (m).

Experiment E2b Asymmetric Hydrogenations of Ketals of6,10-dimethylundec-5-en-2-one or 6,10-dimethylundeca-5,9-dien-2-one

An autoclave was charged with 0.5 mmol of ketals of6,10-dimethylundeca-5,9-dien-2-one or 6,10-dimethylundec-5-en-2-one asindicated in tables 2e to 2h, and with 4 g of the solvent as indicatedin tables 2e to 2h and a solution of the chiral iridium complex offormula (III-F) having the chirality given in tables 2e to 2h at thecentre indicated by * in said formula in the amount indicated in tables2e to 2h. The autoclave was closed and a pressure of 30 bar of molecularhydrogen was applied. The reaction mixture was stirred for 16 hours atroom temperature. Afterwards the pressure was released and the solventwas removed.

The characterization of the hydrogenated ketals is given hereafter.

TABLE 2e Asymmetric hydrogenation of different ketals ofE-6,10-dimethyl-undeca-5,9-dien-2-one (E-GA). 16 17 18 19 Ketal/ketoneE-GA E-GA- E-GA- E-GA- DM neo neo Formula of Ir complex III-F III-FIII-F III-F Configuration of chiral (S) (S) (S) (S) Ir complex at *Amount of chiral Ir 0.5 0.5 0.5 0.5 complex [mol-%] Solvent¹ DCM TFE DCMTFE Hydrogenated ketal/ R-THGA R-THGA- R-THGA- R-THGA- ketone DM neo neoConversion [%] 100 >99 >99 >99 Isomer-Distribution^(2,3) (R) [%] 96.595.3 97.5 98.4 (S) [%] 3.5 4.7 2.5 1.6 Conditions: 0.5 mmol ketal, 4 gsolvent, pressure p(H₂) = 30 bar, 16 h stirring at room temperature.¹TFE = 2,2,2-trifluoroethanol; DCM = dichloromethane ²(R) stands for theR-isomer, (S) stands for the S-isomer of the corresponding ketal of6,10-dimethylundecan-2-one ³is determined as ketone after hydrolysis ofthe ketal

TABLE 2f Asymmetric hydrogenation of different ketals ofZ-6,10-dimethyl-undeca-5,9-dien-2-one (Z-GA). 20 21 22 23 Ketal Z-GA-Z-GA- Z-GA- Z-GA- DM DM neo neo Formula of Ir complex III-F III-F III-FIII-F Configuration of chiral (R) (R) (R) (R) Ir complex at * Amount ofchiral Ir 0.5 0.25 0.25 0.25 complex [mol-%] Solvent¹ DCM TFE DCM TFEHydrogenated ketal R-THGA- R-THGA- R-THGA- R-THGA- DM DM neo neoConversion [%] >99 >99 >99 >99 Isomer-Distribution^(2,3) (R) [%] 98.298.5 97.9 98.6 (S) [%] 1.8 1.5 2.1 1.4 Conditions: 0.5 mmol ketal, 4 gsolvent, pressure p(H₂) = 30 bar, 16 h stirring at room temperature.¹TFE = 2,2,2-trifluoroethanol; DCM = dichloromethane ²(R) stands for theR-isomer, (S) stands for the S-isomer of the corresponding ketal of6,10-dimethylundecan-2-one ³is determined as ketone after hydrolysis ofthe ketal

TABLE 2g Asymmetric hydrogenation of different ketals of E-DHGA. 24 2526 27 Ketal E-DHGA- E-DHGA- E-DHGA- E-DHGA- DM DM neo tfe Formula of Ircomplex III-F III-F III-F III-F Configuration of chiral (S) (S) (S) (S)Ir complex at * Amount of chiral Ir 0.25 0.5 0.25 0.5 complex [mol-%]Solvent¹ DCM TFE DCM TFE Hydrogenated ketal R-THGA- R-THGA- R-THGA-R-THGA- DM DM neo tfe Conversion [%] >99 >99 >99 >99Isomer-Distribution^(2,3) (R) [%] 93.8 94.3 94.7 94.8 (S) [%] 6.2 5.75.3 5.2 ¹TFE = 2,2,2-trifluoroethanol; DCM = dichloromethane ²(R) standsfor the R-isomer, (S) stands for the S-isomer of the corresponding ketalof 6,10-dimethylundecan-2-one ³is determined as ketone after hydrolysisof the ketal

TABLE 2h Asymmetric hydrogenation of different ketals of Z-DHGA. 28 2930 31 Ketal Z-DHGA- Z-DHGA- Z-DHGA- Z-DHGA- DM DM neo neo Formula of Ircomplex III-F III-F III-F III-F Configuration of chiral (R) (R) (R) (R)Ir complex at * Amount of chiral Ir 0.25 0.5 0.5 0.5 complex [mol-%]Solvent¹ DCM TFE DCM TFE Hydrogenated ketal R-THGA- R-THGA- R-THGA-R-THGA- DM DM neo neo Conversion [%] >99 >99 >99 >99Isomer-Distribution^(2,3) (R) [%] 99.2 99.4 97.8 98.0 (S) [%] 0.8 0.62.2 2.0 ¹TFE = 2,2,2-trifluoroethanol; DCM = dichloromethane ²(R) standsfor the R-isomer, (S) stands for the S-isomer of the corresponding ketalof 6,10-dimethylundecan-2-one ³is determined as ketone after hydrolysisof the ketal

Characterization Data (R)-2,2-dimethoxy-6,10-dimethylundecane(R-THGA-DM)

¹H NMR (300 MHz, CDCl₃): δ 0.848 (d, J=6.6 Hz, 3H) superimposed by 0.852(d, J=6.6 Hz, 6H), 1.01-1.41 (m, 11H) superimposed by 1.25 (s, 3H),1.44-1.61 (m, 3H), 3.16 (s, 6H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ 14.1 (1C), 19.6 (1C), 20.9 (1C), 21.7 (1C),22.6 (1C), 22.7 (1C), 24.8 (1C), 27.9 (1C), 32.7 (1C), 36.8 (1C), 37.2(1C), 37.4 (1C), 39.3 (1C), 47.9 (1C), 101.7 (1C) ppm.

MS (EI, m/z): No GC-MS was obtained due to decomposition on the column.

IR (cm⁻¹): 2951 (s), 2927 (m), 2870 (m), 2828 (m), 1723 (w), 1462 (m),1377 (m), 1309 (w), 1256 (m), 1215 (m), 1194 (m), 1172 (m), 1111 (m),1089 (m), 1053 (s), 972 (w), 934 (w), 920 (w), 855 (m), 815 (m), 736(w), 618 (w).

(R)-2-(4,8-dimethylnonyl)-2,5,5-trimethyl-1,3-dioxane (R-THGA-neo)

¹H NMR (300 MHz, CDCl₃): δ 0.87 (d, J=6.6 Hz, 9H), 0.91 (s, 3H), 1.01(s, 3H), 1.04-1.61 (m, 12H) superimposed by 1.36 (s, 3H), 1.61-1.74 (m,2H), AB signal (δA=3.44, δB=3.54, JAB=11.7 Hz, 4H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ 19.7 (1C), 20.4 (1C), 21.0 (1C), 22.56 (1C),22.61 (1C), 22.71 (1C), 22.77 (1C), 24.8 (1C), 28.0 (1C), 30.0 (1C),32.8 (1C), 37.3 (1C), 37.4 (1C), 38.2 (1C), 39.3 (1C), 70.3 (2C), 99.1(1C) ppm.

MS (EI, m/z): 269 [(M-CH₃)⁺, 65), 199 (8), 129 (100), 109 (8), 69 (32),55 (10), 43 (25).

IR (cm⁻¹): 2953 (s), 2925 (s), 2868 (m), 1722 (w), 1464 (m), 1394 (m),1371 (m), 1316 (w), 1258 (m), 1212 (m), 1161 (m), 1141 (m), 1111 (s),1095 (s), 1043 (m), 1020 (m), 951 (m), 925 (m), 907 (m) 870 (m), 855(m), 801 (m), 792 (m), 737 (m), 677 (w), 667 (w).

(R)-6,10-dimethyl-2,2-bis(2,2,2-trifluoroethoxy)undecane (R-THGA-tfe)

¹H NMR (300 MHz, CDCl₃): δ 0.88 (d, J=6.6 Hz, 6H), 0.87 (d, J=6.4 Hz,3H), 1.03-1.23 (m, 5H), 1.39 (s, 3H), 1.38-1.40 (m, 6H), 1.46-1.71 (m,3H), 3.73-3.94 (m, 4H).

¹³C NMR (75 MHz, CDCl₃): δ 19.5 (1C), 21.39 (1C), 21.47 (1C), 22.58(1C), 22.68 (1C), 24.7 (1C), 28.0 (1C), 32.6 (1C), 37.0 (1C), 37.19(1C), 37.23 (1C), 39.3 (1C), 59.2 (q, ²J_(C,F)=32.5 Hz, 2C), 103.6 (1C),124.1 (q, ¹J_(C,F)=279.0 Hz, 2C).

MS (EI, m/z): 365 [(M-CH₃)⁺, 1], 281 (2), 225 [(CF₃CH₂O)₂C—CH₃)⁺, 100],153 (8), 140 (6), 83 (CF₃CH₂ ⁺, 6), 43 (7).

IR (cm⁻¹): 2955 (w), 2929 (w), 2872 (w), 1463 (w), 1419 (w), 1385 (w),1281 (s), 1216 (w), 1156 (s), 1122 (m), 1082 (s), 972 (m), 892 (m), 861(w), 737 (w), 679 (w), 663 (m).

Experiment E2c Hydrolysis of Hydrogenated Ketals of6,10-dimethylundec-5-en-2-one or 6,10-dimethylundeca-5,9-dien-2-one

After the asymmetric hydrogenation of ketals of(6R,10R)-6,10,14-trimethylpentadecan-2-one, the hydrogenated ketalsobtained were hydrolysed to the ketone and yielded(R)-6,10-dimethylundecan-2-one or (S)-6,10-dimethylundecan-2-one,respectively.

Method 1—Neopentyl Ketals, Dimethyl Ketals from Asymmetric HydrogenationReactions in Dichloromethane

A sample of the reaction mixture from the asymmetric hydrogenationreaction (1-2 ml) was stirred with an equal volume of 1M aqueoussolution of hydrochloric acid at room temperature for 1 hour.Dichloromethane (2 ml) was added and the layers were separated. Theaqueous layer was washed with dichloromethane (2 ml) twice. The combinedorganic layers were evaporated under reduced pressure to yield theketone as a colourless to pale-yellow oil. The crude ketone was thenanalysed for purity and isomer ratio.

Method 2—Ethylene Glycol Ketals, Bis(Trifluoroethanol) Ketals andDimethyl Ketals from Asymmetric Hydrogenation Reactions inTrifluoroethanol

A sample of the reaction mixture from the asymmetric hydrogenationreaction (1-2 ml) was stirred with 0.5 ml of a solution of 9:1:0.2 (byvolume) methanol:water:trifluoroacetic acid at 40° C. for 1 hour.Dichloromethane (2 ml) and water (2 ml) were added and the layers wereseparated. The aqueous layer was washed with dichloromethane (2 ml)twice. The combined organic layers were evaporated under reducedpressure to yield the ketone as a colourless to pale-yellow oil. Thecrude ketone was then analysed for purity and isomer ratio.

Experiment E2d Asymmetric Hydrogenations of Ketones and Ketals of6,10-dimethylundec-5-en-2-one or 6,10-dimethylundeca-5,9-dien-2-one

An autoclave vessel was charged under nitrogen with chiral iridiumcomplex of formula (III-F) of the R configuration at the chiral centremarked by *, the ketone or ketal (conc.) as indicated in table 2h or 2i,solvent as indicated in table 2h or 2i). The reaction vessel was closedand pressurized with molecular hydrogen to the pressure (pH₂) indicatedin table 2h or 2i. The reaction mixture was stirred at room temperaturefor the time (t) as indicated in table 2h or 2i under hydrogen. Then thepressure was released and the assay yield and the stereoisomerdistribution of the fully hydrogenated product was determined. In caseof ketals the assay yield and the stereoisomer distribution have beendetermined after the hydrolysis of the ketal by acid as indicated inexperiment E2c. The catalyst loading (S/C) is defined as mmol ketone orketal (“substrate”)/mmol chiral iridium complex.

TABLE 2h Hydrogenation of E-DHGA and of E-DHGA- en. The effect ofketalization. 32 33 Ketone to be hydrogenated E-DHGA Ketal to behydrogenated E-DHGA-en conc.¹ [mol/L] 1.0 0.9 pH₂ [bar] 50 50 t [h] 2020 S/C 10′000 10′000 Solvent TFE TFE Assay yield [area-%] 1 97Isomer-Distribution^(3,4) (R) [%] n.d.² 2.2 (S) [%] n.d.² 97.8 ¹conc. =mol ketone or ketal/L solvent ²n.d. = not determined (due to low assayyield) ³(R) stands for the R-isomer, (S) stands for the S-isomer of theethylene glycol ketal of 6,10-dimethylundecan-2-one ⁴is determined asketone after hydrolysis of the ketal

TABLE 2i Hydrogenation of Z-DHGA and of Z-DHGA-en and of Z-DHGA-neo. Theeffect of ketalization. 34 35 36 37 Ketone to be Z-DHGA hydrogenatedKetal to be Z-DHGA- Z-DHGA- Z-DHGA- hydrogenated en en neo conc.¹[mol/L] 1.0 0.2 0.2 0.2 pH₂ [bar] 50 25 25 25 t [h] 20 15 15 24 S/C5′000 5′000 10′000 10′000 Solvent DCM DCM DCM DCM Assay yield [area-%] 184 39 22 Isomer-Distribution^(3,4) (R) [%] n.d.² 98.6 98.4 95 (S) [%]n.d.² 1.4 1.6 5 ¹conc. = mol ketone or ketal/L solvent (DCM =dichloromethane) ²n.d. = not determined (due to low assay yield) ³(R)stands for the R-isomer, (S) stands for the S-isomer of the ethyleneglycol ketal of 6,10-dimethylundecan-2-one ⁴is determined as ketoneafter hydrolysis of the ketal

Experiment E2e Asymmetric Hydrogenations of6,10-dimethylundec-5-en-2-one or 6,10-dimethylundeca-5,9-dien-2-one orthe Ketals Thereof in the Presence of Additives

The asymmetric hydrogenation was performed as in experiment E2d with thedifference that additives are used for the hydrogenation. The additiveand the amounts used are indicated in table 2j, 2k for the hydrogenationof ketals and in table 21 and 2m for the hydrogenation of ketones.

Preparation of Additives

-   -   MAO/TFE: A 1.6 M MAO (MAO: methylaluminoxane solution in toluene        (0.64 mL) was quenched with 2,2,2-trifluorethanol (TFE) (3.1        mmol), leading to small excess of free TFE.    -   EAO/TFE: A 10 wt % EAO (EAO: ethylaluminoxane solution in        toluene (1 mmol) was quenched with TFE (3.2 mmol), leading to        small excess of free TFE.    -   TMA/TFE: A 2 M TMA (TMA: trimethylaluminum (Al(CH₃)₃)) solution        in heptane (1 mmol) was quenched with TFE (3.1 mmol), leading to        small excess of free TFE.    -   TEA/TFE: A 2 M TEA (TEA: triethylaluminum (Al(CH₂CH₃)₃))        solution in heptane (1 mmol) was quenched with TFE (3.1 mmol),        leading to small excess of free TFE.    -   TMA/BHT/TFE: A 2 M TMA solution in heptane (1 mmol) was quenched        with 2,6-di-tert-butyl-4-methylphenol (BHT) (2 mmol) and        subsequently with TFE (3.1 mmol), leading to small excess of        free TFE.    -   Ti(OCH₂CF₃)₄: Tetraisopropyl orthotitanate (8.1 mmol) was        dissolved in 2,2,2-trifluoroethanol at 50° C. Removal of the        solvent gave Ti(OCH₂CF₃)₄ as a white residue which was isolated        and identified to be Ti(OCH₂CF₃)₄.

These additives were freshly prepared and used either as a heterogeneousmixture at room temperature or homogeneous by heating to a temperaturebetween 50° and 70° C.

The additives tetraisopropyl orthotitanate (Ti(OiPr)₄),tri-isopropylborate (B(OiPr)₃), sodiumtetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBAr_(F)) and triethylborane (TEB) (1 M solution in hexane) are commercially available andwere used as received.

TABLE 2j Hydrogenation of E-DHGA-en at pressure of molecular hydrogen(pH₂) of 50 bar and stirring at room temperature during 20 hours. Theeffect of the additives. 38 39 40 41 42 Ketal to be E- E- E- E- E-hydrogenated DHGA- DHGA- DHGA- DHGA- DHGA- en en en en en conc.¹ [mol/L]0.2 0.7 0.2 2.3 Neat S/C 10′000 30′000 20′000 20′000 20′000 Solvent DCMDCM DCM hexane — Additive — MAO/TFE TMA/TFE TEB B(OiPr)₃ Additive — 10 25 10 concentration [mol-%]² Assay yield 68 99 99 83 97 [area-%] Isomer-Distribution^(3,4) (R) [%] 5 3 2 3.4 2.6 (S) [%] 95 97 98 96.6 97.4¹conc. = mol ketal/L solvent ²relative to the molar amount of E-DHGA-en³(R) stands for the R-isomer, (S) stands for the S-isomer of theethylene glycol ketal of 6,10-dimethylundecan-2-one ⁴is determined asketone after hydrolysis of the ketal.

TABLE 2k Hydrogenation of different ketals of Z-DHGA at pressure ofmolecular hydrogen (pH₂) of 50 bar and stirring at room temperatureduring 20 hours. The effect of the additives. 43 44 45 46 47 48 Ketal tobe Z- Z- Z- Z- Z- Z- hydrogenated DHGA- DHGA- DHGA- DHGA- DHGA- DHGA- enen en en neo neo conc.¹ [mol/L] 0.2 0.2 0.2 0.2 0.2 0.2 S/C 5′000 10′00010′000 52′000 20′000 20′000 Solvent³ DCM DCM TFE TFE TFE TFE Additive —— NaBAr_(F) TMA⁴ — TMA⁴ Additive — — 0.014 100 — 10 concentration[mol-%]² Assay yield 84 39 46 93 4   63 [area-%] Isomer-Distribution^(5,6) (R) [%] 98.6 98.4 97.5 98.1 n.d.⁵ 98.8 (S) [%] 1.41.6 2.5 1.9 n.d.⁵ 1.2 ¹conc. = mol ketal/L solvent ²relative to themolar amount of ketal of Z-DHGA ³TFE = 2,2,2-trifluoroethanol; DCM =dichloromethane ⁴TMA is quenched by adding into the solvent TFE ⁵(R)stands for the R-isomer, (S) stands for the S-isomer of thecorresponding ketal of 6,10-dimethylundecan-2-one ⁶is determined asketone after hydrolysis of the ketal.

TABLE 2l Hydrogenation of E-DHGA at pressure of molecular hydrogen (pH₂)of 50 bar and stirring at room temperature during 20 hours. The effectof the additives. 49 50 51 52 53 Ketone to be E- E- E- E- E-hydrogenated DHGA DHGA DHGA DHGA DHGA conc.¹ [mol/L] 1.0 0.8 0.2 0.2 0.9S/C 10′000 10′000 10′000 10′000 10′000 Solvent TFE TFE TFE TFE TFEAdditive — TMA/TFE TMA/TFE MAO/TFE Ti(OiPr)₄ Additive — 5 5 10 10concentration [mol-%]² Assay yield 1   73 78 53 90 [area-%] Isomer-Distribution^(5, 6) (R) [%] n.d.³ 2.8 2.3 4.2 2.2 (S) [%] n.d.³ 97.297.7 95.8 97.8 ¹conc. = mol ketone/L solvent ²relative to the molaramount of E-DHGA. ³n.d. = not determined (due to low assay yield).

TABLE 2m Hydrogenation of Z-DHGA at pressure of molecular hydrogen (pH₂)of 50 bar and stirring at room temperature during 20 hours. The effectof the additives. 54 55 Ketone to be hydrogenated Z-DHGA Z-DHGA conc.¹[mol/L] 1.0 0.8 S/C 5′000 5′000 Solvent DCM DCM Additive — TMA/TFEAdditive concentration [mol-%]² — 5 Assay yield [area-%] 1   40(R)-6,10-dimethylundecan-2-one [%] n.d. ³ 98.3(S)-6,10-dimethylundecan-2-one [%] n.d. ³ 1.7 ¹conc. = mol ketone/Lsolvent ²relative to the molar amount of Z-DHGA ³ n.d. = not determined(due to low assay yield)..

Chemical Transformation Steps (Step d) Experiment E38 Vinylation of(R)-6,10-dimethylundecan-2-one (Step d1′)

A dried 100 mL four-necked flask equipped with overhead stirrer,thermometer, condenser and argon inlet was evacuated and purged withargon. Vinylmagnesium chloride (23.63 mL of a 1.6 M solution in THF,37.8 mmol, 1.56 eq.) was added at room temperature. A solution(R)-6,10-dimethylundecan-2-one (5.01 g, 24.24 mmol, 96.0%, 1.0 eq.) indry THF (20 mL) was added slowly within 20 min. The exothermic reactionwas maintained between 25 and 30° C. internal temperature by coolingwith an ice bath. After complete addition the reaction was allowed tostir at room temperature for 1 h. Saturated NH₄Cl solution (10 mL) wasadded carefully to quench excess Grignard reagent. Pentane (150 mL),water (150 mL) and brine (150 mL) was added. The organic phase wasextracted with brine (2×150 mL) and the aqueous phase was back-extractedwith pentane (2×150 mL). The combined organic phases were dried (MgSO₄)and concentrated in vacuo, resulting in a colorless oil (5.42 g). Thecrude product was purified by vacuum distillation in a Kugelrohrapparatus. The main fraction distilled at 143° C./3.8⁻² mbar, furnishing(7R)-3,7,11-trimethyldodec-1-en-3-ol as colorless oil with a purity of94.0% (5.15 g, 21.38 mmol, 88% yield).

Experiment E3b Ethynylation of (R)-6,10-dimethylundecan-2-one (Step d1)

(R)-6,10-dimethylundecan-2-one (340 g, 1.70 mol, 1.0 eq., 99.0%) wasadded to an autoclave equipped with thermostat, dosing pump, acetyleneinlet and ammonia inlet. The reactor was sealed, evacuated and flushedwith nitrogen and cooled to 15° C. Ammonia (632 g, 37.2 mol, 22.0 eq.,99.8%) was condensed into the reactor and cooled to 15° C., resulting ina pressure of 8-9 bar. Acetylene was introduced until 12 bar pressurewas reached, followed by a dosed addition of KOH (45 wt.-% in water, 6.6g, 52.9 mmol, 3.1 mol %) at 15° C. The reaction progress was monitoredby GC. After 90 min the reaction mixture was neutralized with aceticacid, and the reactor was subsequently vented at 25° C. The reactionmixture was washed and concentrated in vacuo and purified bydistillation in vacuo furnishing 325 g of(7R)-3,7,11-trimethyldodec-1-yn-3-ol with a purity of 95% (81% yield).

Experiment E3c Hydrogenation of (7R)-3,7,11-trimethyldodec-1-yn-3-ol(Step d2)

(7R)-3,7,11-trimethyldodec-1-yn-3-ol (910 g, 4.06 mol, 1.0 eq., 95%).Lindlar catalyst catalyst (850 mg) were placed into an autoclave. Thereactor was sealed, evacuated, flushed with nitrogen and subsequentlyheated to 45° C. The reactor was evacuated once more and flushed withhydrogen, pressurized to 2 bar. The reaction was stirred for approx. 2-3hours at 45° C. until the calculated amount of molecular hydrogen hadbeen consumed. After filtration 884 g of(7R)-3,7,11-trimethyldodec-1-en-3-ol was obtained with a purity of 91.5%(88% yield).

Experiment E4 Reaction of (7R)-3,7,11-trimethyldodec-1-en-3-ol with2-methoxyprop-1-ene (Step d3)

(7R)-3,7,11-trimethyldodec-1-en-3-ol (640 g, 2.59 mol, 1.0 eq., 91.5%),H₃PO₄ (20 wt % in water, 4.5 g, 8.2 mmol, 0.32 mol %) and isopropenylmethyl ether (600 g, 8.17 mol, 3.2 eq., 98.0%) were placed into a 2 Lautoclave equipped with thermostat, overhead stirrer and 1.1 mdistillation column (Sulzer packing). The reactor was sealed, evacuatedand flushed with nitrogen and subsequently heated to 80° C. The pressurethat built up was slowly vented. The inner temperature was thengradually raised to 160° C. within 1 h. The reaction was stirred for 3 hat 160° C. The reaction mixture was cooled to 30° C., concentrated invacuo and washed with water and NaHCO₃ solution. Then low boilers wereremoved by distillation (jacket temperature 150° C., 1 mbar), furnishing690 g of a mixture of (R,E)-6,10,14-trimethylpentadec-5-en-2-one and(R,Z)-6,10,14-trimethylpentadec-5-en-2-one as residue with a purity of85% (85% yield). The mixture was analyzed by GC to be a mixture of 49%E-isomer and 36% Z-isomer.

Experiment E5 Separation of E/Z Isomer Mixtures of(R,Z)-6,10,14-trimethylpentadec-5-en-2-one (Step e)

The mixture of (R,E)-6,10,14-trimethylpentadec-5-en-2-one and(R,Z)-6,10,14-trimethylpentadec-5-en-2-one 1.94 kg, 36%(R,Z)-6,10,14-trimethylpentadec-5-en-2-one and 49%(R,E)-6,10,14-trimethylpentadec-5-en-2-one was fractionated using theseparation equipment consisting of a still (volume: 9 liter) with afalling film evaporator, a rectifying column (70 mm inner diameter,height 5 m). The column was equipped with a very efficient structuredpacking (Sulzer). The rectification process was operated at a toppressure of approx. 2 mbar and at a column top temperature varied in therange from 95 to 122° C. and the bottom temperature in the still was165° C. The reflux ratio was adjusted to 20. Fractionation of thedistillate stream furnished fractions containing(R,Z)-6,10,14-trimethylpentadec-5-en-2-one (content of Z-isomer=97%). Atthe end (R,E)-6,10,14-trimethylpentadec-5-en-2-one was found left in thestill (content of E-isomer=94%). Both isomers were further purified byfractionation and furnished fractions of both E-isomer and Z-isomer eachwith a purity of 99.5%)

Experiment E6 Asymmetric Hydrogenations of(R,E)-6,10,14-trimethylpentadec-5-en-2-one and(R,Z)-6,10,14-trimethylpentadec-5-en-2-one (Step f)

Both isomers (R,E)-6,10,14-tri methyl pentadec-5-en-2-one) (R,E-THFA)(E/Z=99.5/0.5, R/S=92/8) and (R,Z)-6,10,14-trimethylpentadec-5-en-2-one(R,Z-THFA) (Z/E=99.5/0.5, R/S=92/8) were hydrogenated asymmetrically,separate from each other in the following manner:

A 125 mL autoclave was charged with 7.0 g (26 mmol) of the specificisomer, 50 mL of 2,2,2-trifluoroethanol and a solution of the chiraliridium complex of formula (III-F) having the chirality given in table 3at the centre indicated by * in said formula (42 mg, 0.026 mmol, 0.1 mol%) in anhydrous dichloromethane (4 g). The autoclave was closed and apressure of 50 bar of molecular hydrogen was applied. The reactionmixture was heated to 30° C. whilst stirring for 16 hours. Afterwardsthe pressure was released and the solvent removed. The product formed is(6R,10R)-6,10,14-trimethylpentadecan-2-one. The conversion as well asthe amount of isomers formed is given in table 3.

The products of the two separate asymmetric hydrogenations have beencombined.

In a further experiment in an autoclave 0.25 mmol of(R,E)-6,10,14-trimethylpentadec-5-en-2-one) (R,E-THFA) and 1 mol-%, ofthe Ir complex of the formula (III-D) and 1.25 ml of absolute (dry)dichloromethane were put. The autoclave was closed and a pressure of 50bar of molecular hydrogen was applied. Under stirring the reactionsolution was kept at room temperature for 14 hours. Afterwards thepressure was released and the solvent removed. For determining theconversion the crude product was analysed by achiral gas chromatographywithout any further purification. The amount for the isomers has beendetermined using the above method and given in table 3.

In a further experiment in an autoclave 0.5 mmol of(R,E)-6,10,14-trimethylpentadec-5-en-2-one) (R,E-THFA) and 1 mol-%, ofthe Ir complex of the formula as indicated in table 3′ and 4 g solventas indicated in table 3′ were put. The autoclave was closed and apressure of 30 bar of molecular hydrogen was applied. Under stirring thereaction solution was kept at room temperature for 16 hours. Afterwardsthe pressure was released and the solvent removed. For determining theconversion the crude product was analysed by achiral gas chromatographywithout any further purification. The amount for the isomers has beendetermined using the above method and given in table 3′.

TABLE 3 Asymmetric hydrogenation of R,E-THFA and R,Z-THFA. 56 57 58R,Z-THFA R,E-THFA R,E-THFA Formula of Ir-complex III-F III-F III-DConfiguration of chiral R S S Ir-complex Amount of chiral Ir complex 0.10.1 1 [mol-%] Conversion [%] >99 >99 100 (6R,10R)-6,10,14-trimethyl-87.0 88.4 97.0 pentadecan-2-one [%] (6S,10R)-6,10,14-trimethyl- 5.3 3.71.8 pentadecan-2-one [%] (6R,10S)-6,10,14-trimethyl- 7.7 7.9 1.2*pentadecan-2-one [%] (6S,10S)-6,10,14-trimethyl- 0.0 0.0pentadecan-2-one [%] *(6R,10S) and (6S,10S) isomers determined as sum.

TABLE 3′ Asymmetric hydrogenation of R,E-THFA and R,Z-THFA withdifferent Ir complexes. 59 60 61 62 R,E- R,E- R,E- R,E- THFA THFA THFATHFA Formula of Ir complex III-C III-D III-D III-A′² Configuration ofchiral Ir complex at * S R S S Amount of chiral Ir complex [mol-%] 1 1 11 Solvent¹ DCM TFE DCM DCM Conversion [%] >99 >99 >99 >99Isomer-Distribution (6R,10R)-6,10,14-trimethylpentadecan- 97.3 0.9 96.996.6 2-one [%] (6S,10R)-6,10,14-trimethylpentadecan- 1.3 97.0 1.8 2.02-one [%] (6R,10S)-6,10,14-trimethylpentadecan- 1.4 0 1.3 1.4 2-one [%](6S,10S)-6,10,14-trimethylpentadecan- 0 2.1 0 0 2-one [%] ¹TFE =2,2,2-trifluoroethanol; DCM = dichloromethane ²chiral Ir complex offormula (III-A′):

Experiment E6a Preparation of Ketals of(R,E)-6,10,14-trimethylpentadec-5-en-2-one and(R,Z)-6,10,14-trimethylpentadec-5-en-2-one (Step f_(o))

The dimethyl ketals, neopentyl glycol ketals or bis(trifluoroethyl)ketals, respectively, of (R,E)-6,10,14-trimethylpentadec-5-en-2-one and(R,Z)-6,10,14-trimethylpentadec-5-en-2-one have been obtained in analogyto experiment E2a described above for 6,10-dimethylundec-5-en-2-one or6,10-dimethylundeca-5,9-dien-2-one.

TABLE 3a Preparation of dimethyl and neopentyl glycol ketals of6,10,14-trimethylpentadec-5-en-2-one. R-E-THFA- R-Z-THFA- R-E-THFA-R-Z-THFA- DM DM neo neo Ketone (R,E)- (R,Z)- (R,E)- (R,Z)- 6,10,14-tri-6,10,14-tri- 6,10,14-tri- 6,10,14-tri- methylpenta- methylpenta-methylpenta- methylpenta- dec-5-en- dec-5-en- dec-5-en- dec-5-en- 2-one2-one 2-one 2-one Ketal (R,E)-2,2-di- (R,Z)-2,2-di- (R,E)-2,5,5-(R,Z)-2,5,5- methoxy- methoxy- trimethyl-2- trimethyl-2- 6,10,14-tri-6,10,14-tri- (4,8,12-tri- (4,8,12-tri- methylpenta- methylpenta-methyltridec- methyltridec- dec-5-ene dec-5-ene 3-en-1-yl)- 3-en-1-yl)-1,3-dioxane 1,3-dioxane Yield 92 87 83 86 [%] E/Z 99.5/0.5 3.6/96.499.8/0.2 4/96

Characterization Data(R,E)-2,2-dimethoxy-6,10,14-trimethylpentadec-5-ene (R-E-THFA-DM)

¹H NMR (300 MHz, CDCl₃): δ 0.84 (d, J=6.6 Hz, 3H), superimposed by 0.86(d, J=6.6 Hz, 6H), 0.99-1.44 (m, 11H), superimposed by 1.28 (s. 3H),1.52 (tqq, J=6.6, 6.6, 6.6 Hz, 1H), 1.60 (s, 3H), 1.60-1.66 (m, 2H),1.90-2.05 (m, 4H), 3.18 (s, 6H), 5.10 (tq, J=7.1, 1.1 Hz, 1H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ 16.3 (1C), 20.1 (1C), 21.3 (1C), 23.0 (1C),23.1 (1C), 23.2 (1C), 25.2 (1C), 25.7 (1C), 28.4 (1C), 33.1 (1C), 36.9(1C), 37.1 (1C), 37.7 (1C), 39.8 (1C), 40.3 (1C), 48.4 (2C), 101.9 (1C),124.0 (1C), 136.0 (1C) ppm.

MS (EI, m/z): No GC-MS was obtained due to decomposition on the column.

IR (cm⁻¹): 2952 (m), 2927 (s), 2869 (m), 2828 (w), 1461 (m), 1377 (m),1301 (w), 1262 (m), 1222 (m), 1197 (m), 1172 (m), 1120 (m), 1101 (m),1076 (m), 1054 (s), 930 (w), 854 (m), 737 (w), 620 (w).

(R,Z)-2,2-dimethoxy-6,10,14-trimethylpentadec-5-ene (R-Z-THFA-DM)

¹H NMR (300 MHz, CDCl₃): δ 0.85 (d, J=6.4 Hz, 3H), superimposed by 0.87(d, J=6.4 Hz, 6H), 1.01-1.27 (m, 7H), 1.28 (s, 3H), 1.29-1.44 (m, 4H),1.53 (dqq, J=6.5, 6.5 Hz, 6.5 Hz, 1H), 1.58-1.66 (m, 2H), 1.68 (q, J=1.1Hz, 3H), 1.91-2.08 (m, 4H), 3.18 (s, 6H), 5.11 (t, J=6.8 Hz, 1H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ) 19.7 (1C), 20.9 (1C), 22.60 (1C), 22.69(1C), 22.71 (1C), 23.4 (1C), 24.8 (1C), 25.5 (1C), 28.0 (1C), 32.0 (1C),32.7 (1C), 36.8 (1C), 37.0 (1C), 37.3 (1C), 39.3 (1C), 48.0 (2C), 101.5(1C), 124.3 (1C), 135.9 (1C) ppm.

MS (EI, m/z): No GC-MS was obtained due to decomposition on the column.

IR (cm⁻¹): 2952 (m), 2927 (m), 2869 (m), 2828 (w), 1462 (m), 1376 (m),1301 (w), 1261 (w), 1197 (w), 1172 (m), 1119 (m), 1098 (m), 1074 (m),1054 (s), 1022 (w), 854 (m), 736 (w), 622 (w).

(R,E)-2,5,5-trimethyl-2-(4,8,12-trimethyltridec-3-en-1-yl)-1,3-dioxane(R-E-THFA-neo)

¹H NMR (300 MHz, CDCl₃): δ 0.84 (d, J=6.4 Hz, 3H), 0.86 (d, J=6.6 Hz,6H), 0.92 (s, 3H), 0.99 (s, 3H), superimposed by 0.97-1.44 (m, 11H),superimposed by 1.37 (s, 3H), 1.52 (qqt, J=6.9, 6.9, 6.9 Hz, 1H), 1.60(s, 3H), 1.67-1.76 (m, 2H), 1.93 (t, J=7.4 Hz, 2H), 2.03-2.18 (m, 2H),AB signal (δ_(A)=3.45, δ_(B)=3.52, J_(AB)=11.4 Hz, 4H), 5.12 (tq, J=7.2,1.0 Hz, 1H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ 15.8 (1C), 19.7 (1C), 20.9 (1C), 22.0 (1C),22.6 (2C), 22.7 (2C), 24.8 (1C), 25.3 (1C), 27.9 (1C), 29.9 (1C), 32.6(1C), 36.6 (1C), 37.3 (1C), 37.4 (1C), 39.3 (1C), 39.9 (1C), 70.3 (2C),98.8 (1C), 123.8 (1C), 135.5 (1C) ppm.

MS (EI, m/z): 352 (M⁺, 4), 337 [(M-CH₃)⁺, 8), 265 (6), 129 (100), 95(10), 69 (25), 43 (25).

IR (cm⁻¹): 2953 (s), 2926 (s), 2867 (m), 1462 (m), 1394 (w), 1369 (m),1270 (w), 1249 (m), 1211 (m), 1187 (w), 1119 (s), 1088 (s), 1043 (m),1021 (m), 951 (w), 925 (w), 907 (w), 862 (m), 791 (w), 738 (w), 678 (w).

(R,Z)-2,5,5-trimethyl-2-(4,8,12-trimethyltridec-3-en-1-yl)-1,3-dioxane(R-Z-THFA-neo)

¹H NMR (300 MHz, CDCl₃): δ 0.84 (d, J=6.4 Hz, 3H), superimposed by 0.86(d, J=6.6 Hz, 6H), 0.93 (s, 3H), 0.97 (s, 3H), 1.00-1.42 (m, 11H),superimposed by 1.36 (s, 3H), 1.52 (qqt, J=6.7, 6.7, 6.7 Hz, 1H),1.63-1.76 (m, 2H), 1.67 (s, 3H), 1.94-2.15 (m, 4H), AB signal(δ_(A)=3.45, δ_(B)=3.51, J_(AB)=11.1 Hz, 4H), 5.12 (t, J=7.1 Hz, 1H)ppm.

¹³C NMR (75 MHz, CDCl₃): δ 19.6 (1C), 21.1 (1C), 21.9 (1C), 22.60 (2C),22.67 (2C), 22.69 (1C), 23.4 (1C), 24.8 (1C), 25.4 (1C), 27.9 (1C), 29.9(1C), 32.0 (1C), 32.7 (1C), 36.9 (1C), 37.3 (1C), 39.3 (1C), 70.3 (2C),98.8 (1C), 124.6 (1C), 135.7 (1C) ppm.

MS (EI, m/z): 352 (M⁺, 3), 337 [(M-CH₃)⁺, 9), 265 (6), 129 (100), 95(10), 69 (24), 43 (25).

IR (cm⁻¹): 2953 (s), 2926 (s), 2860 (m), 1463 (m), 1394 (w), 1371 (m),1270 (w), 1250 (w), 1211 (m), 1188 (w), 1117 (s), 1086 (s), 1043 (m),1022 (w), 951 (w), 925 (w), 907 (w), 855 (m), 792 (w), 737 (w), 667 (w).

Experiment E6b Asymmetric Hydrogenations of Ketals of(R,E)-6,10,14-trimethylpentadec-5-en-2-one and(R,Z)-6,10,14-trimethylpentadec-5-en-2-one

An autoclave was charged with 0.5 mmol of ketals of(R,E)-6,10,14-trimethylpentadec-5-en-2-one and(R,Z)-6,10,14-trimethylpentadec-5-en-2-one as indicated in tables 3b and3c, and with 4 g of the solvent as indicated in tables 3b and 3c and asolution of the chiral iridium complex of formula (III-F) having thechirality given in tables 3b and 3c at the centre indicated by * in saidformula in the amount indicated in tables 3b and 3c. The autoclave wasclosed and a pressure of 30 bar of molecular hydrogen was applied. Thereaction mixture was stirred for 16 hours at room temperature.Afterwards the pressure was released and the solvent was removed.

Hydrogenation of(R,E)-6,10,14-trimethyl-2,2-bis(2,2,2-trifluoroethoxy)pentadec-5-eneyielded(6R,10R)-6,10,14-trimethyl-2,2-bis(2,2,2-trifluoroethoxy)pentadecaneusing the Ir complex of formula (III-F) of the S configuration at thechiral centre marked by *.

The characterization of the hydrogenated ketals is given hereafter.

TABLE 3b Asymmetric hydrogenation of different ketals of(R,E)-6,10,14-trimethylpentadec-5-en-2-one leading to(6R,10R)-6,10,14-trimethylpentadecan-2-one. 63 64 65 Ketal to behydrogenated R-E-THFA- R-E-THFA- R-E-THFA- DM DM neo Formula of Ircomplex III-F III-F III-F Configuration of chiral (S) (S) (S) Ir complexat * Amount of chiral Ir 0.25 0.25 0.5 complex [mol-%] Solvent¹ DCM TFEDCM Conversion [%] >99 >99 >99 Isomer-Distribution^(2,3) (RR) [%] 90.088.7 90.6 ((SS) + (RS)) [%] 8.0 8.7 9.4 (SR) [%] 2.0 2.6 0.0 Conditions:0.5 mmol ketal, 4 g solvent, pressure p(H₂) = 30 bar, 16 h stirring atroom temperature ¹TFE = 2,2,2-trifluoroethanol; DCM = dichloromethane²(SS) stands for the (6S,10S)-isomer, (RR) stands for the(6R,10R)-isomer, (SR) stands for the (6S,10R)-isomer, (RS) stands forthe (6R,10S)-isomer of the corresponding ketal of6,10,14-trimethylpentadecan-2-one ³is determined as ketone afterhydrolysis of the ketal

TABLE 3c Asymmetric hydrogenation of different ketals of(R,Z)-6,10,14-trimethylpentadec-5-en-2-one leading to(6R,10R)-6,10,14-trimethylpentadecan-2-one. 66 67 68 69 Ketal to behydrogenated R-Z- R-Z- R-Z- R-Z- THFA- THFA- THFA- THFA- DM DM neo neoFormula of Ir complex III-F III-F III-F III-F Configuration of chiral(R) (R) (R) (R) Ir complex at * Amount of chiral Ir 0.5 0.5 0.5 0.5complex [mol-%] Solvent¹ DCM TFE DCM TFE Conversion [%] >99 >99 >99 >99Isomer-Distribution^(2,3) (RR) [%] 86.3 87.4 86.8 85.5 ((SS) + (RS)) [%]8.2 7.5 8.2 9.4 (SR) [%] 5.5 5.1 5.0 5.1 Conditions: 0.5 mmol ketal, 4 gsolvent, pressure p(H₂) = 30 bar, 16 h stirring at room temperature ¹TFE= 2,2,2-trifluoroethanol; DCM = dichloromethane ²(SS) stands for the(6S,10S)-isomer, (RR) stands for the (6R,10R)-isomer, (SR) stands forthe (6S,10R)-isomer, (RS) stands for the (6R,10S)-isomer of thecorresponding ketal of 6,10,14-trimethylpentadecan-2-one ³is determinedas ketone after hydrolysis of the ketal.

Characterization Data(6R,10R)-2,2-dimethoxy-6,10,14-trimethylpentadecane (RR18-DM)

¹H NMR (300 MHz, CDCl₃): δ 0.83-0.80 (m, 12H), 0.98-1.45 (m, 21H),1.46-1.65 (m, 3H), 3.18 (s, 6H).

¹³C NMR (75 MHz, CDCl₃): δ 19.68 (1C), 19.73 (1C), 21.0 (1C), 21.7 (1C),22.6 (1C), 22.7 (1C), 24.5 (1C), 24.8 (1C), 28.0 (1C), 32.72 (1C), 32.78(1C), 36.8 (1C), 37.28 (1C), 37.33 (1C), 37.36 (1C), 37.41 (1C), 39.4(1C), 48.0 (2C), 101.7 (1C) ppm.

IR (cm⁻¹): 2951 (s), 2926 (s), 2869 (s), 2828 (m), 1734 (w), 1723 (w),1216 (w), 1463 (s), 1377 (s), 1308 (w), 1255 (m), 1215 (m), 1172 (s),1105 (s), 1090 (s), 1054 (s), 971 (w), 933 (w), 860 (s), 815 (m), 736(w) 618 (w).

2,5,5-trimethyl-2-((4R,8R)-4,8,12-trimethyltridecyl)-1,3-dioxane(RR18-neo)

¹H NMR (300 MHz, CDCl₃): δ 0.78-0.95 (m, 15H), 0.95-1.61 (m, 19H),superimposed by 1.01 (s, 3H), 1.36 (s, 3H), 1.63-1.74 (m, 2H), AB signal(δ_(A)=3.44, δ_(B)=3.55, J_(AB)=11.7 Hz, 4H) ppm.

¹³C NMR (75 MHz, CDCl₃): δ 19.72 (1C), 19.74 (1C), 20.4 (1C), 20.9 (1C),22.56 (1C), 22.62 (1C), 22.72 (1C), 22.77 (1C), 24.5 (1C), 24.8 (1C),28.0 (1C), 30.0 (1C), 32.8 (1C), 32.8 (1C), 37.28 (1C), 37.35 (1C),37.42 (2C), 38.2 (1C), 39.4 (1C), 70.3 (2C), 99.1 (1C) ppm.

MS (EI, m/z): 339 [(M-CH₃)⁺, 83], 269 (5), 129 (100), 69 (21), 43 (18).

IR (cm⁻¹): 2952 (s), 2925 (s), 2867 (m), 1463 (m), 1394 (m), 1372 (m),1258 (m), 1211 (m), 1189 (w), 1141 (w), 1100 (s), 1043 (m), 1020 (m),951 (w), 925 (w), 907 (m), 858 (m), 792 (w), 737 (w), 677 (w).

(6R,10R)-6,10,14-trimethyl-2,2-bis(2,2,2-trifluoroethoxy)pentadecane(RR18-tfe)

¹H NMR (600 MHz, CDCl₃): δ 0.86 (d, J=6.6 Hz, 3H), 0.879 (d, J=6.6 Hz,3H), 0.882 (d, J=6.6 Hz, 3H), 0.884 (d, J=6.6 Hz, 3H), 1.03-1.46 (m,18H), superimposed by 1.40 (s, 3H), 1.54 (qqt, J=6.6, 6.6, 6.6 Hz, 1H),1.60-1.70 (m, 2H), 3.77-3.90 (m, 4H) ppm.

¹³C NMR (151 MHz, CDCl₃): δ 19.6 (1C), 19.7 (1C), 21.4 (1C), 21.5 (1C),22.6 (1C), 22.7 (1C), 24.5 (1C), 24.8 (1C), 28.0 (1C), 32.6 (1C), 32.8(1C), 37.0 (1C), 37.24 (1C), 37.30 (1C), 37.34 (1C), 37.43 (1C), 39.4(1C), 59.2 (q, ²J_(C,F)=35.0 Hz, 2C), 103.6 (1C), 124.0 (q,¹J_(C,F)=277.0 Hz, 2C) ppm.

MS (EI, m/z): 435 [(M-CH₃)⁺, 1], 351 (1), 250 (1), 225[(CF₃CH₂O)₂C—CH₃)⁺, 100], 153 (7), 140 (5), 83 (CF₃CH₂ ⁺, 3), 43 (6).

IR (cm⁻¹): 2954 (m), 2927 (m), 2871 (w), 1463 (w), 1419 (w), 1384 (w),1281 (s), 1215 (w), 1157 (s), 1123 (m), 1082 (s), 972 (s), 892 (m), 861(w), 737 (w), 679 (w), 663 (m).

Experiment E6c Hydrolysis of Hydrogenated Ketals of(R,E)-6,10,14-trimethylpentadec-5-en-2-one and(R,Z)-6,10,14-trimethylpentadec-5-en-2-one

After the asymmetric hydrogenation of the corresponding ketals of(R,E)-6,10,14-trimethylpentadec-5-en-2-one and(R,Z)-6,10,14-trimethylpentadec-5-en-2-one, the hydrogenated ketalsobtained were hydrolyzed to the ketone and yielded(6R,10R)-6,10,14-trimethylpentadecan-2-one.

The hydrogenated ketals have been hydrolyzed as described in ExperimentE2c

Formation of (R,R)-isophytol Experiment E6-I Ethynylation of(6R,10R)-6,10,14-trimethylpentadecan-2-one (Step g)

(6R,10R)-6,10,14-trimethylpentadecan-2-one (35.0 g, 129 mmol, 1.0 eq.,98.8%) was added to an autoclave equipped with thermostat, dosing pump,acetylene inlet and ammonia inlet. The reactor was sealed, evacuated,then flushed with nitrogen and cooled to 15° C. Ammonia (715 g, 45.0mol, 326 eq., 99.8%) was condensed into the reactor and cooled to 15°C., resulting in a pressure of 8-9 bar. Acetylene was introduced until12 bar was reached, followed by a dosed addition of KOH (40 wt % inwater, 5.0 g, 35.6 mmol, 28 mol %) at 15° C. The reaction progress wasmonitored by GC. At the desired conversion (after approx. 2 h), thereaction mixture was neutralized with acetic acid, and the reactor wassubsequently vented at 25° C. The reaction mixture was washed andconcentrated in vacuo and purified by distillation in vacuo furnishing26.9 g (7R,11R)-3,7,11,15-tetramethylhexadec-1-yn-3-ol with a purity of98.8 area % (70% yield).

Experiment E6-II Hydrogenation of(6R,10R)-6,10,14-trimethylpentadecan-2-one in the Presence of a LindlarCatalyst (Step h)

(7R,11R)-3,7,11,15-tetramethylhexadec-1-yn-3-ol (10 g, 33.4 mmol, 98.4%purity), dissolved in heptane (40 g) and Lindlar catalyst (850 mg) wereplaced into an autoclave. The reactor was sealed, flushed with nitrogenand subsequently heated to 85° C. When the desired temperature wasreached, the reaction was pressurized with 2 bar hydrogen. The reactionwas stirred for approximately 22 hours at this temperature until therequired amount of hydrogen gas was consumed. After filtration, thecrude product was combined with a second reaction batch. 11.9 g of thecrude material was purified by distillation, furnishing 11.1 g of(R,R)-isophytol (97.6% purity by GC, 88% overall yield).

Experiment E6-III Vinylation of(6R,10R)-6,10,14-trimethylpentadecan-2-one (Step h′)

A dried 100 mL four-necked flask equipped with overhead stirrer,thermometer, condenser and argon inlet was evacuated and purged withargon. Vinylmagnesium chloride (18.3 mL of a 1.6 M solution in THF, 29.0mmol, 1.59 eq.) was added at room temperature. A solution of(6R,10R)-6,10,14-trimethylpentadecan-2-one (5.00 g, 18.3 mmol, 98.2%,1.0 eq.) in dry THF (20 mL) was added slowly within 25 min. Theexothermic reaction was maintained between 25 and 30° C. internaltemperature by cooling with an ice bath. After complete addition thereaction was allowed to stir at room temperature for 1 h. SaturatedNH₄Cl solution (10 mL) was added carefully to quench excess Grignardreagent. Pentane (150 mL), water (150 mL) and brine (150 mL) was added.The organic phase was extracted with brine (2×150 mL) and the aqueousphase was back-extracted with pentane (2×150 mL). The combined organicphases were dried (MgSO₄) and concentrated in vacuo, resulting in acolorless oil (5.58 g). The crude product was purified by vacuumdistillation in a Kugelrohr apparatus. The main fraction distilled at143° C./3.5×10⁻² mbar, furnishing (R,R)-isophytol(=(7R,11R)-3,7,11,15-tetramethylhexadec-1-en-3-ol) as colorless oil witha purity of 99.3% (5.271 g, 96% yield).

Experiment E7 Formation of (2-ambo)-α-tocopherol (Step m)

(R,R)-isophytol (=(7R,11R)-3,7,11,15-tetramethylhexadec-1-en-3-ol) wascondensed with 2,3,5-trimethylbenzene-1,4-diol(=2,3,5-trimethylhydroquinone) in the presence of a condensationcatalyst to (2-ambo)-α-tocopherol according to the procedure disclosedin WO 2005/121115 A1.

Experiment E8 Formation of (2R,4′R,8′R)-α-tocopherol (Step n)

As shown in FIG. 7, (2-ambo)-α-tocopherol was separated by means ofchromatographic separation using a chiral phase. The preparativechromatography yielded (2R,4′R,8′R)-α-tocopherol and(2S,4′R,8′R)-α-tocopherol:

The (2-ambo)-α-tocopherol of experiment E7 was analyzed by HPLC (Column:Daicel Chiracel® OD-H, 250 mm×4.6 mm; eluent 0.5% ethanol in n-heptane;flow 1 ml/min; detection 220 nm, 2 μl injection. FIG. 7b ) shows thischromatogram (Retention time 7.2 resp. 8.2 min, 50.2:49.2).

A solution of 140 mg (2-ambo)-α-tocopherol in heptane was injected andtwo peaks with retention time at maximum of 13.4 min (1) (50.1%) and15.0 min (2) (49.9%) were separated by the preparative HPLC separation.FIG. 7a ) shows the chromatogram of the preparative HPLC separation.

After evaporation to dryness and dissolution the two collected fractionshave been reanalysed on an analytical column (Daicel Chiracel® OD-H, 250mm×4.6 mm; eluent 0.5% ethanol in n-heptane; flow 1 ml/min; detection220 nm, 2 μl injection). FIG. 7c ), respectively FIG. 7d ), show thechromatogram of the first fraction, respectively the second fraction.The isomeric ratios of the two isomers (Retention time 7.2 min, resp.8.2 min) in said fractions are 99.5:0.5 (FIG. 7c )) and 0.8:99.2 (FIG.7d ), respectively. Hence, the two isomers have been separation bypreparative chromatography almost completely.

The isomers have been identified to be (2R,4′R,8′R)-α-tocopherol(retention time 7.2 min) and (2S,4′R,8′R)-α-tocopherol (retention time8.2 min).

Experimental Details for Chromatography of Experiment E8:

Preparative separations were performed on an Agilent 1100 series HPLCsystem consisting of an Agilent 1100 degasser, Agilent 1100 preparativepump. Agilent 1100 diode array detector. Agilent 1100 MPS G2250Aautosampler/fraction collector controlled by chemstation/CC-modesoftware package.

HPLC Conditions for Preparative Separation:

Column: Daicel Chiracel® OD-H, 250 mm×20 mm; eluent 0.5% isopropanol,0.2% acetic acid in n-heptane; flow 13 ml/min; detection 220 nm, 400 μlinjection.

The invention claimed is:
 1. A process of manufacturing(6R,10R)-6,10,14-trimethylpentadecan-2-one in a multistep synthesis from6,10-dimethylundec-5-en-2-one or 6,10-dimethylundeca-5,9-dien-2-onecomprising the sequential steps of: a) providing a mixture of(E)-6,10-dimethylundec-5-en-2-one and (Z)-6,10-dimethylundec-5-en-2-oneor a mixture of (E)-6,10-dimethylundeca-5,9-dien-2-one and(Z)-6,10-dimethylundeca-5,9-dien-2-one; b) separating one isomer of6,10-dimethylundec-5-en-2-one or of 6,10-dimethylundeca-5,9-dien-2-onefrom the mixture of step a); c) conducting asymmetric hydrogenationusing molecular hydrogen in the presence of a chiral iridium complex andyielding (R)-6,10-dimethylundecan-2-one; d) chemically transforming(R)-6,10-dimethylundecan-2-one to a mixture of(R,E)-6,10,14-trimethylpentadec-5-en-2-one and(R,Z)-6,10,14-trimethylpentadec-5-en-2-one; e) separating one isomer of(R)-6,10,14-trimethylpentadec-5-en-2-one from the mixture obtained instep d); and f) conducting asymmetric hydrogenation using molecularhydrogen in the presence of a chiral iridium complex and yielding(6R,10R)-6,10,14-trimethylpentadecan-2-one, wherein step d) is practicedby: d1) ethynylation of (R)-6,10-dimethylundecan-2-one using ethyne inthe presence of a basic substance to yield(7R)-3,7,11-trimethyldodec-1-yn-3-ol; and d2) hydrogenation of(7R)-3,7,11-trimethyldodec-1-yn-3-ol with molecular hydrogen in thepresence of a Lindlar catalyst to yield(7R)-3,7,11-trimethyldodec-1-en-3-ol; or step d) is practiced by: d1′)vinylation of (R)-6,10-dimethylundecan-2-one by addition of a vinylGrignard reagent to yield (7R)-3,7,11-trimethyldodec-1-en-3-ol; followedby either d3) reacting (7R)-3,7,11-trimethyldodec-1-en-3-ol with2-methoxyprop-1-ene to yield a mixture of(R,E)-6,10,14-trimethylpentadec-5-en-2-one and(R,Z)-6,10,14-trimethylpentadec-5-en-2-one; or d3′) reacting(7R)-3,7,11-trimethyldodec-1-en-3-ol with an alkyl acetoacetate ordiketene in the presence of a base and/or an acid to yield a mixture of(R,E)-6,10,14-trimethylpentadec-5-en-2-one and(R,Z)-6,10,14-trimethylpentadec-5-en-2-one.
 2. The process according toclaim 1, which further comprises a step c_(o)) before step c): c_(o))forming of a ketal of the isomer of 6,10-dimethylundec-5-en-2-one or of6,10-dimethylundeca-5,9-dien-2-one separated in step b), and wherein theketal of 6,10-dimethylundec-5-en-2-one or of6,10-dimethylundeca-5,9-dien-2-one in step c) is asymmetricallyhydrogenated and after the asymmetric hydrogenation the hydrogenatedketal is hydrolysed to the ketone thereby yielding(R)-6,10-dimethylundecan-2-one.
 3. The process according to claim 1,wherein the process further comprises a step f_(o)) before the step f)of: f_(o)) forming a ketal of the isomer of(R)-6,10,14-trimethylpentadec-5-en-2-one separated in step e), andwherein step f) comprises asymmetrically hydrogenating the ketal of(R)-6,10,14-trimethylpentadec-5-en-2-one and then subsequently after theasymmetric hydrogenation, hydrolysing the hydrogenated ketal to theketone to thereby yield (6R,10R)-6,10,14-trimethylpentadecan-2-one. 4.The process according to claim 1, wherein the asymmetric hydrogenationin step c) and/or step f) takes place in the presence of an additivewhich is selected from the group consisting of organic sulfonic acids,transition metal salts of organic sulfonic acids, metal alkoxides,aluminoxanes, alkyl aluminoxanes and B(R)_((3-v))(OZ)_(v), wherein vstands for 0, 1, 2 or 3, R stands for F, a C₁₋₆-alkyl, a halogenatedC₁₋₆-alkyl, an aryl or halogenated aryl group, and Z stands aC₁₋₆-alkyl, a halogenated C₁₋₆-alkyl, an aryl or halogenated aryl group.5. The process according to claim 1, wherein the separation of isomersin step b) and/or e) is done by distillation.
 6. The process accordingto claim 5, wherein the distillation is done in the presence of acis/trans isomerization catalyst.
 7. The process according to claim 1,which further comprises isomerizing residual isomer in the presence of acis/trans isomerization catalyst, and respectively adding the isomerizedresidual isomer to the corresponding mixture of isomers provided bysteps a) and d).
 8. The process according to claim 1, wherein the chiraliridium complex in steps c) and/or f) is a chiral iridium complex offormula (III-0)

wherein P-Q-N stands for a chelating organic ligand comprising astereogenic centre or has planar or axial chirality and has a nitrogenand phosphorous atom as binding site to the iridium centre of thecomplex; Y¹, Y², Y³ and Y⁴ independently from each other are hydrogenatoms, C₁₋₁₂-alkyl, C₅₋₁₀-cycloalkyl, or aromatic group; or at least twoof Y¹, Y², Y³ and Y⁴ form together at least a two-valent bridged groupof at least 2 carbon atoms; with the proviso that Y¹, Y², Y³ and Y⁴ arenot all hydrogen atoms; and Y^(⊖) is an anion selected from the groupconsisting of halide, PF₆ ⁻, SbF₆ ⁻,tetra(3,5-bis(trifluoromethyl)phenyl)borate (BAr_(F) ⁻), BF₄ ⁻,perfluorinated sulfonates, ClO₄ ⁻, Al(OC₆F₅)₄ ⁻, Al(OC(CF₃)₃)₄ ⁻,N(SO₂CF₃)₂ ⁻N(SO₂C₄F₉)₂ ⁻ and B(C₆F₅)₄ ⁻.
 9. The process according toclaim 1, wherein the chiral iridium complex in steps c) and/or f) is achiral iridium complex of formula (III)

wherein n is 1, 2 or 3; X¹ and X² are independently from each otherhydrogen atoms, C₁₋₄-alkyl, C₅₋₇-cycloalkyl, adamantyl, phenyloptionally substituted with one to three C₁₋₅-alkyl, C₁₋₄-alkoxy,C₁₋₄-perfluoroalkyl groups and/or one to five halogen atoms, benzyl,1-naphthyl, 2-naphthyl, 2-furyl or ferrocenyl; Z¹ and Z² areindependently from each other hydrogen atoms, C₁₋₅-alkyl or C₁₋₅-alkoxygroups or Z¹ and Z² stand together for a bridging group forming a 5 to 6membered ring; Y^(⊖) is an anion selected from the group consisting ofhalide, PF₆ ⁻, SbF₆ ⁻,tetra(3,5-bis(trifluoromethyl)phenyl)borate(BAr_(F) ⁻), BF₄ ⁻,perfluorinated sulfonates, ClO₄ ⁻, Al(OC₆F₆)₄ ⁻, Al(OC(CF₃)₃)₄ ⁻,N(SO₂CF₃)₂ ⁻N(SO₂C₄F₉)₂ ⁻ and B(C₆F₆)₄ ⁻; R¹ represents either phenyl oro-tolyl or m-tolyl or p-tolyl or a group of formula (IVa) or (IVb) or(IVc):

wherein R² and R³ represent either both H or a C₁₋₄-alkyl group or ahalogenated C₁₋₄-alkyl group or represent a divalent group formingtogether a 6-membered cycloaliphatic or an aromatic ring whichoptionally is substituted by halogen atoms or by C₁₋₄-alkyl groups or byC_(1∝)-alkoxy groups; R⁴ and R⁵ represent either both H or a C₁₋₄-alkylgroup or a halogenated C₁₋₄-alkyl group or a divalent group formingtogether a 6-membered cycloaliphatic or an aromatic ring whichoptionally is substituted by halogen atoms or by C₁₋₄-alkyl groups or byC₁₋₄-alkoxy groups; R⁶ and R⁷ and R⁸ represent each a C₁₋₄-alkyl groupor a halogenated C₁₋₄-alkyl group; R⁹ and R¹⁹ represent either both H ora C₁₋₄-alkyl group or a halogenated C₁₋₄-alkyl group or a divalent groupforming together a 6-membered cycloaliphatic or an aromatic ring whichoptionally is substituted by halogen atoms or by C₁₋₄-alkyl groups or byC₁₋₄-alkoxy groups; and wherein the symbol * represents a stereogeniccentre of the complex of formula (III).
 10. The process according toclaim 9, wherein the chiral iridium complex of formula (III) used instep c) and/or f) for the asymmetric hydrogenation has theS-configuration at the stereogenic centre indicated by the symbol * incase (E)-6,10-dimethylundec-5-en-2-one or(E)-6,10-dimethylundeca-5,9-dien-2-one, or ketals thereof, or(R,E)-6,10,14-trimethylpentadec-5-en-2-one, or ketals thereof, are to behydrogenated; or the chiral iridium complex of formula (III) used instep c) and/or f) for the asymmetric hydrogenation has theR-configuration at the stereogenic centre indicated by the symbol * incase (Z)-6,10-dimethylundec-5-en-2-one or(Z)-6,10-dimethylundeca-5,9-dien-2-one, or ketals thereof, or(R,Z)-6,10,14-trimethylpentadec-5-en-2-one, or ketals thereof, are to behydrogenated.
 11. A process of manufacturing (R,R)-isophytol((3RS,7R,11R)-3,7,11,15-tetramethylhexadec-1-en-3-ol) comprisingmanufacturing (6R,10R)-6,10,14-trimethylpentadecan-2-one according toclaim 1, followed by the steps of: g) ethynylation of(6R,10R)-6,10,14-trimethylpentadecan-2-one using ethyne in the presenceof a basic substance to yield(7R,11R)-3,7,11,15-tetramethylhexadec-1-yn-3-ol; and either h)hydrogenation of (7R,11R)-3,7,11,15-tetramethylhexadec-1-yn-3-ol withmolecular hydrogen in the presence of a Lindlar catalyst to yield(R,R)-isophytol; or h′) vinylation of(6R,10R)-6,10,14-trimethylpentadecan-2-one by addition of a vinylGrignard reagent to yield (R,R)-isophytol.
 12. A process ofmanufacturing compound of formula (V) comprising manufacturing(6R,10R)-6,10,14-trimethylpentadecan-2-one according to 1, followed bythe steps of: g) ethynylation of(6R,10R)-6,10,14-trimethylpentadecan-2-one using ethyne in the presenceof a basic substance to yield(7R,11R)-3,7,11,15-tetramethylhexadec-1-yn-3-ol; and either h)hydrogenation of (7R,11R)-3,7,11,15-tetramethylhexadec-1-yn-3-ol withmolecular hydrogen in the presence of a Lindlar catalyst to yield(R,R)-isophytol; or h′) vinylation of(6R,10R)-6,10,14-trimethylpentadecan-2-one by addition of a vinylGrignard reagent to yield (R,R)-isophytol; and then subsequentlyfollowed by the step of: m) condensing (R,R)-isophytol with a compoundof formula (VI) to yield the compound of formula (V) being an isomericmixture in view of the chirality at the centre indicated by the symbol#;

and wherein the symbol # represents a stereogenic centre.
 13. A processof manufacturing compound of formula (V-A) comprising manufacturing(6R,10R)-6,10,14-trimethylpentadecan-2-one according to claim 1,followed by the steps of: g) ethynylation of(6R,10R)-6,10,14-trimethylpentadecan-2-one using ethyne in the presenceof a basic substance to yield(7R,11R)-3,7,11,15-tetramethylhexadec-1-yn-3-ol; and either h)hydrogenation of (7R,11R)-3,7,11,15-tetramethylhexadec-1-yn-3-ol withmolecular hydrogen in the presence of a Lindlar catalyst to yield(R,R)-isophytol; or h′) vinylation of(6R,10R)-6,10,14-trimethylpentadecan-2-one by addition of a vinylGrignard reagent to yield (R,R)-isophytol; and then subsequentlyfollowed by the steps of: m) condensing (R,R)-isophytol with compound offormula (VI) to yield compound of formula (V) being an isomeric mixturein view of the chirality at the centre indicated by the symbol #;

wherein R¹¹, R¹³ and R¹⁴ are independently from each other hydrogen ormethyl groups; and wherein the symbol # represents a stereogenic centre;and n) isolating the compound of formula (V-A) from the isomeric mixtureof formula (V)


14. A composition comprising: at least one ketal of formula (XI) or(XII); and at least one chiral iridium complex,

wherein a wavy line represents a carbon-carbon bond which is linked tothe adjacent carbon-carbon double bond so as to have the carbon-carbondouble bond either in the Z or in the E-configuration; and wherein thedouble bond having dotted lines

in formula (XI) represent either a single carbon-carbon bond or a doublecarbon-carbon bond; and wherein the symbol

represents a stereogenic centre; and wherein Q¹ and Q² stand eitherindividually or both for a C₁-C₁₀ alkyl group or a halogenated C₁-C₁₀alkyl group; or Q¹ and Q² form together a C₂-C₆ alkylene group or aC₆-C₈ cycloalkylene group.
 15. A ketal of formula (XX-A), (XX-B), (XX-C)or (XX-D):

wherein the double bond having dotted lines (

) in the above formulae represents either a single carbon-carbon bond ora double carbon-carbon bond; and wherein a wavy line represents acarbon-carbon bond which is linked to an adjacent single carbon bond (

representing—) or to an adjacent carbon-carbon double bond (

representing═) so as to have the carbon-carbon double bond either in theZ or in the E-configuration.
 16. The process according to claim 8,wherein Y^(O) is F₃C—SO₃ ⁻ or F₉C₄—SO₃ ⁻.
 17. The process according toclaim 9, wherein Y^(O) is F₃C—SO₃ ⁻ or F₉C₄—SO₃ ⁻.